Pyrazole-substituted arylamides as P2X3 and P2X2/3 antagonists

ABSTRACT

Compounds of the formula I: 
                         
or a pharmaceutically acceptable salt thereof, wherein, R 1  is optionally substituted pyrazolyl, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are as defined herein. Also disclosed are methods of using the compounds for treating diseases associated with P2X 3  and/or a P2X 2/3  receptor antagonists and methods of making the compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 13/847,742 filed Mar. 20, 2013 which is a continuation of U.S. Ser. No. 12/317,008 filed Dec. 17, 2008, now U.S. Pat. No. 8,440,673, which claims benefit under 35 U.S.C. 119(e) of U.S. Provisional Application No. 61/007,960, filed Dec. 17, 2007 all of which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

This invention pertains to compounds useful for treatment of diseases associated with P2X purinergic receptors, and more particularly to P2X₃ and/or P2X_(2/3) antagonists usable for treatment of genitourinary, pain, inflammatory, gastrointestinal and respiratory diseases, conditions and disorders.

BACKGROUND OF THE INVENTION

The urinary bladder is responsible for two important physiological functions: urine storage and urine emptying. This process involves two main steps: (1) the bladder fills progressively until the tension in its walls rises above a threshold level; and (2) a nervous reflex, called the micturition reflex, occurs that empties the bladder or, if this fails, at least causes a conscious desire to urinate. Although the micturition reflex is an autonomic spinal cord reflex, it can also be inhibited or mediated by centers in the cerebral cortex or brain.

Purines, acting via extracellular purinoreceptors, have been implicated as having a variety of physiological and pathological roles. (See, Burnstock (1993) Drug Dev. Res. 28:195-206.) ATP, and to a lesser extent, adenosine, can stimulate sensory nerve endings resulting in intense pain and a pronounced increase in sensory nerve discharge. ATP receptors have been classified into two major families, the P2Y- and P2X-purinoreceptors, on the basis of molecular structure, transduction mechanisms, and pharmacological characterization. The P2Y-purinoreceptors are G-protein coupled receptors, while the P2X-purinoreceptors are a family of ATP-gated cation channels. Purinergic receptors, in particular, P2X receptors, are known to form homomultimers or heteromultimers. To date, cDNAs for several P2X receptors subtypes have been cloned, including: six homomeric receptors, P2X₁; P2X₂; P2X₃; P2X₄; P2X₅; and P2X₇; and three heteromeric receptors P2X_(2/3), P2X_(4/6), P2X_(1/5) (See, e.g., Chen, et al. (1995) Nature 377:428-431; Lewis, et al. (1995) Nature 377:432-435; and Burnstock (1997) Neurophamacol. 36:1127-1139). The structure and chromosomal mapping of mouse genomic P2X₃ receptor subunit has also been described (Souslova, et al. (1997) Gene 195:101-111). In vitro, co-expression of P2X₂ and P2X₃ receptor subunits is necessary to produce ATP-gated currents with the properties seen in some sensory neurons (Lewis, et al. (1995) Nature 377:432-435).

P2X receptor subunits are found on afferents in rodent and human bladder urothelium. Data exists suggesting that ATP may be released from epithelial/endothelial cells of the urinary bladder or other hollow organs as a result of distention (Burnstock (1999) J. Anatomy 194:335-342; and Ferguson et al. (1997) J. Physiol. 505:503-511). ATP released in this manner may serve a role in conveying information to sensory neurons located in subepithelial components, e.g., suburothelial lamina propria (Namasivayam, et al. (1999) BJU Intl. 84:854-860). The P2X receptors have been studied in a number of neurons, including sensory, sympathetic, parasympathetic, mesenteric, and central neurons (Zhong, et al. (1998) Br. J. Pharmacol. 125:771-781). These studies indicate that purinergic receptors play a role in afferent neurotransmission from the bladder, and that modulators of P2X receptors are potentially useful in the treatment of bladder disorders and other genitourinary diseases or conditions.

Recent evidence also suggests a role of endogenous ATP and purinergic receptors in nociceptive responses in mice (Tsuda, et al. (1999) Br. J. Pharmacol. 128:1497-1504). ATP-induced activation of P2X receptors on dorsal root ganglion nerve terminals in the spinal cord has been shown to stimulate release of glutamate, a key neurotransmitter involved in nociceptive signaling (Gu and MacDermott, Nature 389:749-753 (1997)). P2X₃ receptors have been identified on nociceptive neurons in the tooth pulp (Cook et al., Nature 387:505-508 (1997)). ATP released from damaged cells may thus lead to pain by activating P2X₃ and/or P2X_(2/3) containing receptors on nociceptive sensory nerve endings. This is consistent with the induction of pain by intradermally applied ATP in the human blister-base model (Bleehen, Br J Pharmacol 62:573-577 (1978)). P2X antagonists have been shown to be analgesic in animal models (Driessen and Starke, Naunyn Schmiedebergs Arch Pharmacol 350:618-625 (1994)). This evidence suggests that P2X₂ and P2X₃ are involved in nociception, and that modulators of P2X receptors are potentially useful as analgesics.

Other researchers have shown that P2X₃ receptors are expressed in human colon, and are expressed at higher levels in inflamed colon than in normal colon (Y. Yiangou et al, Neurogastroenterol Mot (2001) 13:365-69). Other researchers have implicated the P2X₃ receptor in detection of distension or intraluminal pressure in the intestine, and initiation of reflex contractions (X. Bian et al., J Physiol (2003) 551.1:309-22), and have linked this to colitis (G. Wynn et al., Am J Physiol Gastrointest Liver Physiol (2004) 287:G647-57).

Inge Brouns et al. (Am J Respir Cell Mol Biol (2000) 23:52-61) found that P2X₃ receptors are expressed in pulmonary neuroepithelial bodies (NEBs), implicating the receptor in pain transmission in the lung. More recently, others have implicated P2X₂ and P2X₃ receptors in pO₂ detection in pulmonary NEBs (W. Rong et al., J Neurosci (2003) 23(36):11315-21).

There is accordingly a need for compounds that act as modulators of P2X receptors, including antagonists of P2X₃ and P2X_(2/3) receptors, as well as a need for methods of treating diseases, conditions and disorders mediated by P2X₃ and/or P2X_(2/3) receptors. The present invention satisfies these needs as well as others.

SUMMARY OF THE INVENTION

The invention provides compounds of the formula I:

or pharmaceutically acceptable salts thereof, wherein:

R¹ is optionally substituted pyrazolyl;

R² is optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl or optionally substituted thiophenyl;

R³ is:

-   -   hydrogen;     -   C₁₋₆alkyl;     -   hetero-C₁₋₆alkyl; or     -   cyano;

R⁴ is:

-   -   hydrogen;     -   C₁₋₆alkyl; or     -   hetero-C₁₋₆alkyl;

or R³ and R⁴ together with the atom to which they are attached may form a C₃₋₆ carbocyclic ring;

R⁵ is:

-   -   C₁₋₆alkyl;     -   hetero-C₁₋₆alkyl;     -   halo-C₁₋₆alkyl;     -   N—C₁₋₆alkylamino;     -   N,N-di-(C₁₋₆alkyl)-amino;     -   C₃₋₇cycloalkyl;     -   aryl;     -   heteroaryl;     -   heterocyclyl;     -   C₃₋₇cycloalkyl-C₁₋₆alkyl;     -   heteroaryl-C₁₋₆alkyl;     -   heterocyclyl-C₁₋₆alkyl;     -   aryl-C₁₋₆alkyl;     -   aryloxy-C₁₋₆alkyl;     -   —(CR^(a)R^(b))_(m)—C(O)—R⁸ wherein:         -   m is 0 or 1;         -   R^(a) and R^(b) each independently is:             -   hydrogen; or             -   C₁₋₆alkyl; and         -   R⁸ is:             -   hydrogen;             -   C₁₋₆alkyl;             -   hetero-C₁₋₆alkyl;             -   C₃₋₇cycloalkyl;             -   aryl;             -   heteroaryl;             -   heterocyclyl;             -   C₃₋₇cycloalkyl-C₁₋₆alkyl;             -   aryl-C₁₋₆alkyl;             -   heteroaryl-C₁₋₆alkyl;             -   heterocyclyl-C₁₋₆alkyl;             -   C₃₋₇cycloalkyloxy;             -   aryloxy;             -   heteroaryloxy;             -   heterocyclyloxy;             -   C₃₋₇cycloalkyloxy-C₁₋₆alkyl;             -   aryloxy-C₁₋₆alkyl;             -   heteroaryloxy-C₁₋₆alkyl;             -   heterocyclyloxy-C₁₋₆alkyl; or             -   —NR⁹R¹⁰, wherein:                 -   R⁹ is:                 -    hydrogen; or                 -    C₁₋₆alkyl; and                 -   R¹⁰ is:                 -    hydrogen;                 -    C₁₋₆alkyl;                 -    hetero-C₁₋₆alkyl;                 -    C₃₋₇cycloalkyl;                 -    aryl;                 -    heteroaryl;                 -    heterocyclyl;                 -    C₃₋₇cycloalkyl-C₁₋₆alkyl;                 -    aryl-C₁₋₆alkyl;                 -    heteroaryl-C₁₋₆alkyl; or                 -    heterocyclyl-C₁₋₆alkyl;

or R⁴ and R⁵ together with the atom to which they are attached may form a C₃₋₆ carbocyclic ring that is optionally substituted with hydroxy;

or R⁴ and R⁵ together with the atom to which they are attached may form a C₄₋₆ heterocyclic ring containing one or two heteroatoms each independently selected from O, N and S;

or R³, R⁴ and R⁵ together with the atom to which they are attached may form a six-membered heteroaryl containing one or two nitrogen atoms, and which is optionally substituted with halo, amino or C₁₋₆alkyl; and

R⁶, R⁷ and R⁸ each independently is:

-   -   hydrogen     -   C₁₋₆alkyl;     -   C₁₋₆alkyloxy;     -   halo;     -   C₁₋₆haloalkyl; or     -   cyano.

The invention also provides and pharmaceutical compositions comprising the compounds, methods of using the compounds, and methods of preparing the compounds.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless otherwise stated, the following terms used in this Application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms “a”, “an,” and “the” include plural referents unless the context clearly dictates otherwise.

“Agonist” refers to a compound that enhances the activity of another compound or receptor site.

“Alkyl” means the monovalent linear or branched saturated hydrocarbon moiety, consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms. “Lower alkyl” refers to an alkyl group of one to six carbon atoms, i.e. C₁-C₆alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

“Alkenyl” means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like.

“Alkynyl” means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g., ethynyl, propynyl, and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and the like.

“Alkoxy” and “alkyloxy”, which may be used interchangeably, mean a moiety of the formula —OR, wherein R is an alkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

“Alkoxyalkyl” means a moiety of the formula R^(a)—O—R^(b)—, where R^(a) is alkyl and R^(b) is alkylene as defined herein. Exemplary alkoxyalkyl groups include, by way of example, 2-methoxyethyl, 3-methoxypropyl, 1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl, and 1-(2-methoxyethyl)-3-methoxypropyl.

“Alkylcarbonyl” means a moiety of the formula —R′—R″, where R′ is oxo and R″ is alkyl as defined herein.

“Alkylsulfonyl” means a moiety of the formula —R′—R″, where R′ is —SO₂— and R″ is alkyl as defined herein.

“Alkylsulfonylalkyl means a moiety of the formula —R′—R″—R′″ where where R′ is alkylene, R″ is —SO₂— and R′″ is alkyl as defined herein.

“Alkylamino means a moiety of the formula —NR—R′ wherein R is hydrogen or alkyl and R′ is alkyl as defined herein.

“Alkoxyamino” means a moiety of the formula —NR—OR′ wherein R is hydrogen or alkyl and R′ is alkyl as defined herein.

“Alkylsulfanyl” means a moiety of the formula —SR wherein R is alkyl as defined herein.

“Aminoalkyl” means a group —R—R′ wherein R′ is amino and R is alkylene as defined herein. “Aminoalkyl” includes aminomethyl, aminoethyl, 1-aminopropyl, 2-aminopropyl, and the like. The amino moiety of “aminoalkyl” may be substituted once or twice with alkyl to provide “alkylaminoalkyl” and “dialkylaminoalkyl” respectively. “Alkylaminoalkyl” includes methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminoethyl and the like. “Dialkylaminoalkyl” includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N-methyl-N-ethylaminoethyl, and the like.

“Aminoalkoxy” means a group —OR—R′ wherein R′ is amino and R is alkylene as defined herein.

“Alkylsulfonylamido” means a moiety of the formula —NR′SO₂—R wherein R is alkyl and R′ is hydrogen or alkyl.

“Aminocarbonyloxyalkyl” or “carbamylalkyl” means a group of the formula —R—O—C(O)—NR′R″ wherein R is alkylene and R′, R″ each independently is hydrogen or alkyl as defined herein.

“Alkynylalkoxy” means a group of the formula —O—R—R′ wherein R is alkylene and R′ is alkynyl as defined herein.

“Antagonist” refers to a compound that diminishes or prevents the action of another compound or receptor site.

“Aryl” means a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-, bi- or tricyclic aromatic ring. The aryl group can be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, including partially hydrogenated derivatives thereof, each being optionally substituted.

“Arylalkyl” and “Aralkyl”, which may be used interchangeably, mean a radical—R^(a)R^(b) where R^(a) is an alkylene group and R^(b) is an aryl group as defined herein; e.g., phenylalkyls such as benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like are examples of arylalkyl.

“Arylsulfonyl means a group of the formula —SO₂—R wherein R is aryl as defined herein.

“Aryloxy” means a group of the formula —O—R wherein R is aryl as defined herein.

“Aralkyloxy” means a group of the formula —O—R—R″ wherein R is alkylene and R′ is aryl as defined herein.

“Cyanoalkyl”” means a moiety of the formula —R′—R″, where R′ is alkylene as defined herein and R″ is cyano or nitrile.

“Cycloalkyl” means a monovalent saturated carbocyclic moiety consisting of mono- or bicyclic rings. Cycloalkyl can optionally be substituted with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino, unless otherwise specifically indicated. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated derivatives thereof.

“Cycloalkylalkyl” means a moiety of the formula —R′—R″, where R′ is alkylene and R″ is cycloalkyl as defined herein.

“Heteroalkyl” means an alkyl radical as defined herein wherein one, two or three hydrogen atoms have been replaced with a substituent independently selected from the group consisting of —OR^(a), —NR^(b)R^(c), and —S(O)_(n)R^(d) (where n is an integer from 0 to 2), with the understanding that the point of attachment of the heteroalkyl radical is through a carbon atom, wherein R^(a) is hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; R^(b) and R^(c) are independently of each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; and when n is 0, R^(d) is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl, and when n is 1 or 2, R^(d) is alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, or dialkylamino. Representative examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

“Heteroaryl” means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. The heteroaryl ring may be optionally substituted as defined herein. Examples of heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like, including partially hydrogenated derivatives thereof, each optionally substituted.

Heteroarylalkyl” or “heteroaralkyl” means a group of the formula —R—R′ wherein R is alkylene and R′ is heteroaryl as defined herein.

“Heteroarylsulfonyl means a group of the formula —SO₂—R wherein R is heteroaryl as defined herein.

“Heteroaryloxy” means a group of the formula —O—R wherein R is heteroaryl as defined herein.

“Heteroaralkyloxy” means a group of the formula —O—R—R″ wherein R is alkylene and R′ is heteroaryl as defined herein.

The terms “halo”, “halogen” and “halide”, which may be used interchangeably, refer to a substituent fluoro, chloro, bromo, or iodo.

“Haloalkyl” means alkyl as defined herein in which one or more hydrogen has been replaced with same or different halogen. Exemplary haloalkyls include —CH₂Cl, —CH₂CF₃, —CH₂CCl₃, perfluoroalkyl (e.g., —CF₃), and the like.

“Haloalkoxy” means a moiety of the formula —OR, wherein R is a haloalkyl moiety as defined herein. An exemplary haloalkoxy is difluoromethoxy.

“Heterocycloamino” means a saturated ring wherein at least one ring atom is N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

“Heterocyclyl” means a monovalent saturated moiety, consisting of one to three rings, incorporating one, two, or three or four heteroatoms (chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may be optionally substituted as defined herein. Examples of heterocyclyl moieties include, but are not limited to, optionally substituted piperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl, benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone, dihydroquinolinyl, dihydrisoquinolinyl, tetrahydroquinolinyl, tetrahydrisoquinolinyl, and the like.

“Heterocyclylalkyl” means a moiety of the formula —R—R′ wherein R is alkylene and R′ is heterocyclyl as defined herein.

“Heterocyclyloxy” means a moiety of the formula —OR wherein R is heterocyclyl as defined herein.

“Heterocyclylalkoxy” means a moiety of the formula —OR—R′ wherein R is alkylene and R′ is heterocyclyl as defined herein.

“Hydroxyalkoxy” means a moiety of the formula —OR wherein R is hydroxyalkyl as defined herein.

“Hydroxyalkylamino” means a moiety of the formula —NR—R′ wherein R is hydrogen or alkyl and R′ is hydroxyalkyl as defined herein.

“Hydroxyalkylaminoalkyl” means a moiety of the formula —R—NR′—R″ wherein R is alkylene, R′ is hydrogen or alkyl, and R″ is hydroxyalkyl as defined herein.

“Hydroxycarbonylalkyl” or “carboxyalkyl” means a group of the formula —R—(CO)—OH where R is alkylene as defined herein.

“Hydroxyalkyloxycarbonylalkyl” or “hydroxyalkoxycarbonylalkyl” means a group of the formula —R—C(O)—O—R—OH wherein each R is alkylene and may be the same or different.

“Hydroxyalkyl” means an alkyl moiety as defined herein, substituted with one or more, preferably one, two or three hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy group. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl

“Hydroxycycloalkyl” means a cycloalkyl moiety as defined herein wherein one, two or three hydrogen atoms in the cycloalkyl radical have been replaced with a hydroxy substituent. Representative examples include, but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the like.

“Urea”or “ureido” means a group of the formula —NR′—C(O)—NR″R′″ wherein R′, R″ and R′″ each independently is hydrogen or alkyl.

“Carbamate” means a group of the formula —O—C(O)—NR′R″ wherein R′ and R″ each independently is hydrogen or alkyl.

“Carboxy” means a group of the formula —O—C(O)—OH.

“Sulfonamido” means a group of the formula —SO₂—NR′R″ wherein R′, R″ and R′″ each independently is hydrogen or alkyl.

“Optionally substituted”, when used in association with “aryl”, phenyl”, “heteroaryl” “cycloalkyl” or “heterocyclyl”, means an aryl, phenyl, heteroaryl, cycloalkyl or heterocyclyl which is optionally substituted independently with one to four substituents, preferably one or two substituents selected from alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy, heteroalkyl, —COR, —SO₂R (where R is hydrogen, alkyl, phenyl or phenylalkyl), —(CR′R″)_(n)—COOR (where n is an integer from 0 to 5, R′ and R″ are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), or —(CR′R″)_(n)—CONR^(a)R^(b) (where n is an integer from 0 to 5, R′ and R″ are independently hydrogen or alkyl, and R^(a) and R^(b) are, independently of each other, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl). Certain preferred optional substituents for “aryl”, phenyl”, “heteroaryl” “cycloalkyl” or “heterocyclyl” include alkyl, halo, haloalkyl, alkoxy, cyano, amino and alkylsulfonyl. More preferred substituents are methyl, fluoro, chloro, trifluoromethyl, methoxy, amino and methanesulfonyl.

“Leaving group” means the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under substitution reaction conditions. Examples of leaving groups include, but are not limited to, halogen, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like.

“Modulator” means a molecule that interacts with a target. The interactions include, but are not limited to, agonist, antagonist, and the like, as defined herein.

“Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.

“Disease” and “Disease state” means any disease, condition, symptom, disorder or indication.

“Inert organic solvent” or “inert solvent” means the solvent is inert under the conditions of the reaction being described in conjunction therewith, including for example, benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tent-butanol, dioxane, pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert solvents.

“Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound. Such salts include:

acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphtoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like; or

salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

The preferred pharmaceutically acceptable salts are the salts formed from acetic acid, hydrochloric acid, sulphuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc, and magnesium.

It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt.

“Protective group” or “protecting group” means the group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Certain processes of this invention rely upon the protective groups to block reactive nitrogen and/or oxygen atoms present in the reactants. For example, the terms “amino-protecting group” and “nitrogen protecting group” are used interchangeably herein and refer to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures. Exemplary nitrogen protecting groups include, but are not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. The artisan in the art will know how to chose a group for the ease of removal and for the ability to withstand the following reactions.

“Solvates” means solvent additions forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H₂O, such combination being able to form one or more hydrate.

“Subject” means mammals and non-mammals. Mammals means any member of the mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term “subject” does not denote a particular age or sex.

“Disorders of the urinary tract” or “uropathy” used interchangeably with “symptoms of the urinary tract” means the pathologic changes in the urinary tract. Examples of urinary tract disorders include, but are not limited to, incontinence, benign prostatic hypertrophy (BPH), prostatitis, detrusor hyperreflexia, outlet obstruction, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urge incontinence, urethritis, prostatodynia, cystitis, idiophatic bladder hypersensitivity, and the like.

“Disease states associated with the urinary tract” or “urinary tract disease states” or “uropathy” used interchangeably with “symptoms of the urinary tract” mean the pathologic changes in the urinary tract, or dysfunction of urinary bladder smooth muscle or its innervation causing disordered urinary storage or voiding. Symptoms of the urinary tract include, but are not limited to, overactive bladder (also known as detrusor hyperactivity), outlet obstruction, outlet insufficiency, and pelvic hypersensitivity.

“Overactive bladder” or “detrusor hyperactivity” includes, but is not limited to, the changes symptomatically manifested as urgency, frequency, altered bladder capacity, incontinence, micturition threshold, unstable bladder contractions, sphincteric spasticity, detrusor hyperreflexia (neurogenic bladder), detrusor instability, and the like.

“Outlet obstruction” includes, but is not limited to, benign prostatic hypertrophy (BPH), urethral stricture disease, tumors, low flow rates, difficulty in initiating urination, urgency, suprapubic pain, and the like.

“Outlet insufficiency” includes, but is not limited to, urethral hypermobility, intrinsic sphincteric deficiency, mixed incontinence, stress incontinence, and the like.

“Pelvic Hypersensitivity” includes, but is not limited to, pelvic pain, interstitial (cell) cystitis, prostatodynia, prostatitis, vulvadynia, urethritis, orchidalgia, overactive bladder, and the like.

“Respiratory disorder” refers to, without limitation, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and the like.

“Gastrointestinal disorder” (“GI disorder”) refers to, without limitation, Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, pain associated with GI distension, and the like.

“Pain” includes, without limitation, inflammatory pain; surgical pain; visceral pain; dental pain; premenstrual pain; central pain; pain due to burns; migraine or cluster headaches; nerve injury; neuritis; neuralgias; poisoning; ischemic injury; interstitial cystitis; cancer pain; viral, parasitic or bacterial infection; post-traumatic injury; or pain associated with irritable bowel syndrome.

“Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The “therapeutically effective amount” will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.

The terms “those defined above” and “those defined herein” when referring to a variable incorporates by reference the broad definition of the variable as well as preferred, more preferred and most preferred definitions, if any.

“Treating” or “treatment” of a disease state includes:

-   -   (i) preventing the disease state, i.e. causing the clinical         symptoms of the disease state not to develop in a subject that         may be exposed to or predisposed to the disease state, but does         not yet experience or display symptoms of the disease state.     -   (ii) inhibiting the disease state, i.e., arresting the         development of the disease state or its clinical symptoms, or     -   (iii) relieving the disease state , i.e., causing temporary or         permanent regression of the disease state or its clinical         symptoms.

The terms “treating”, “contacting” and “reacting” when referring to a chemical reaction means adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture

which ultimately leads to the formation of the indicated and/or the desired product.

Nomenclature and Structures

In general, the nomenclature used in this Application is based on AUTONOM™ v.4.0, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature. Chemical structures shown herein were prepared using ISIS® version 2.2. Any open valency appearing on a carbon, oxygen sulfur or nitrogen atom in the structures herein indicates the presence of a hydrogen atom unless indicated otherwise. Where a nitrogen-containing heteroaryl ring is shown with an open valency on a nitrogen atom, and variables such as R^(a), R^(b) or R^(c) are shown on the heteroaryl ring, such variables may be bound or joined to the open valency nitrogen. Where a chiral center exists in a structure but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral center are encompassed by the structure. Where a structure shown herein may exist in multiple tautomeric forms, all such tautomers are encompassed by the structure.

All patents and publications identified herein are incorporated herein by reference in their entirety.

Compounds of the Invention

The invention provides compounds of the formula I:

or pharmaceutically acceptable salts thereof, wherein:

R¹ is optionally substituted pyrazolyl;

R² is optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl or optionally substituted thiophenyl;

R³ is:

-   -   hydrogen;     -   C₁₋₆alkyl;     -   hetero-C₁₋₆alkyl; or     -   cyano;

R⁴ is:

-   -   hydrogen;     -   C₁₋₆alkyl; or     -   hetero-C₁₋₆alkyl;

or R³ and R⁴ together with the atom to which they are attached may form a C₃₋₆ carbocyclic ring;

R⁵ is:

-   -   C₁₋₆alkyl;     -   hetero-C₁₋₆alkyl;     -   halo-C₁₋₆alkyl;     -   N—C₁₋₆alkylamino;     -   N,N-di-(C₁₋₆alkyl)-amino;     -   C₃₋₇cycloalkyl;     -   aryl;     -   heteroaryl;     -   heterocyclyl;     -   C₃₋₇cycloalkyl-C₁₋₆alkyl;     -   heteroaryl-C₁₋₆alkyl;     -   heterocyclyl-C₁₋₆alkyl;     -   aryl-C₁₋₆alkyl;     -   aryloxy-C₁₋₆alkyl;     -   —(CR^(a)R^(b))_(m)—C(O)—R⁸ wherein:         -   m is 0 or 1;         -   R^(a) and R^(b) each independently is:             -   hydrogen; or             -   C₁₋₆alkyl; and         -   R⁸ is:             -   hydrogen;             -   C₁₋₆alkyl;             -   hetero-C₁₋₆alkyl;             -   C₃₋₇cycloalkyl;             -   aryl;             -   heteroaryl;             -   heterocyclyl;             -   C₃₋₇cycloalkyl-C₁₋₆alkyl;             -   aryl-C₁₋₆alkyl;             -   heteroaryl-C₁₋₆alkyl;             -   heterocyclyl-C₁₋₆alkyl;             -   C₃₋₇cycloalkyloxy;             -   aryloxy;             -   heteroaryloxy;             -   heterocyclyloxy;             -   C₃₋₇cycloalkyloxy-C₁₋₆alkyl;             -   aryloxy-C₁₋₆alkyl;             -   heteroaryloxy-C₁₋₆alkyl;             -   heterocyclyloxy-C₁₋₆alkyl; or             -   —NR⁹R¹⁰, wherein:                 -   R⁹ is:                 -    hydrogen; or                 -    C₁₋₆alkyl; and                 -   R¹⁰ is:                 -    hydrogen;                 -    C₁₋₆alkyl;                 -    hetero-C₁₋₆alkyl;                 -    C₃₋₇cycloalkyl;                 -    aryl;                 -    heteroaryl;                 -    heterocyclyl;                 -    C₃₋₇cycloalkyl-C₁₋₆alkyl;                 -    aryl-C₁₋₆alkyl;                 -    heteroaryl-C₁₋₆alkyl; or                 -    heterocyclyl-C₁₋₆alkyl;

or R⁴ and R⁵ together with the atom to which they are attached may form a C₃₋₆ carbocyclic ring that is optionally substituted with hydroxy;

or R⁴ and R⁵ together with the atom to which they are attached may form a C₄₋₆ heterocyclic ring containing one or two heteroatoms each independently selected from O, N and S;

or R³, R⁴ and R⁵ together with the atom to which they are attached may form a six-membered heteroaryl containing one or two nitrogen atoms, and which is optionally substituted with halo, amino or C₁₋₆alkyl; and

R⁶, R⁷ and R⁸ each independently is:

-   -   hydrogen     -   C₁₋₆alkyl;     -   C₁₋₆alkyloxy;     -   halo;     -   C₁₋₆haloalkyl; or     -   cyano.

In certain embodiments of formula I, R¹ is optionally substituted pyrazol-1-yl.

In certain embodiments of formula I, R¹ is optionally substituted pyrazol-3-yl.

In certain embodiments of formula I, R¹ is optionally substituted pyrazol-4-yl.

In many embodiments of formula I, R¹ is pyrazolyl optionally substituted once, twice or three times, and more preferably once, with C₁₋₆alkyl.

In many embodiments of formula I, R¹ is pyrazolyl optionally substituted with C₁₋₆alkyl or halo-C₁₋₆alky.

In many embodiments of formula I, R¹ is pyrazolyl optionally substituted once with C₁₋₆alkyl or halo-C₁₋₆alky.

In certain embodiments of formula I, R¹ is pyrazolyl optionally substituted once, twice or three times, preferably once, with C₁₋₆alkyl, halo-C₁₋₆alkyl, hetero-C₁₋₆alkyl, C₁₋₆alkoxy, heterocyclyl-C₁₋₆alkyl, C₁₋₆alkoxycarbonyl, C₁₋₆alkylaminocarbonyl, di-C₁₋₆alkylaminocarbonyl, phenyl, heterocyclyl, C₃₋₆-cycloalkyl, C₃₋₆cycloalkyl-C₁₋₆alkyl or cyano.

In certain embodiments of formula I, R¹ is pyrazolyl optionally substituted once or twice, preferably once, with C₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy, heterocyclyl-C₁₋₆alkyl, C₁₋₆alkoxy-carbonyl, C₁₋₆alkylamino-carbonyl, di-C₁₋₆alkylamino-carbonyl, C₃₋₆-cycloalkyl or C₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is pyrazolyl optionally substituted once with C₁₋₆alkyl, halo-C₁₋₆alkyl, hetero-C₁₋₆alkyl, C₁₋₆alkoxy, phenyl, heterocyclyl, C₃₋₆-cycloalkyl, C₃₋₆cycloalkyl-C₁₋₆alkyl or cyano.

In certain embodiments of formula I, R¹ is pyrazolyl optionally substituted once with halo-C₁₋₄alkyl.

In certain embodiments of formula I, R¹ is pyrazolyl substituted once with halo-C₁₋₄alkyl.

In certain embodiments of formula I, R¹ is pyrazolyl substituted once with hetero-C₁₋₆alkyl selected from hydroxy-C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl, C₁₋₆alkylamino-C₁₋₆alkyl, or N,N-di-(C₁₋₆alkyl)-amino-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is pyrazolyl optionally substituted once with methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, phenyl, trifluoromethyl, difluoromethyl, fluoromethyl, pentafluoro-ethyl, 1,1-difluoro-ethyl, 2,2-difluoroethyl, ethoxy-carbonyl, methylamino-carbonyl, dimethylamino-carbonyl, isopropylamino-carbonyl, 3-methyl-oxetan-3-yl, 1-methoxy-ethyl, 1-ethoxy-ethyl, 2-methoxy-1-methyl-ethyl, 1-hydroxy-ethyl, isopropoxy, 1-methyl-azetidin-2-yl, 1-dimethylamino-ethyl or dimethylamino-methyl.

In certain embodiments of formula I, R¹ is pyrazolyl optionally substituted once with methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, trifluoromethyl, pentafluoro-ethyl, ethoxy-carbonyl, methylamino-carbonyl, dimethylamino-carbonyl, isopropylamino-carbonyl, or 3-methyl-oxetan-3-yl.

In certain embodiments of formula I, R¹ is pyrazolyl substituted once with C₁₋₆alkyl selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopropylmethyl.

In certain embodiments of formula I, R¹ is pyrazolyl optionally substituted once with halo-C₁₋₆alkyl selected from trifluoromethyl, difluoromethyl, fluoromethyl, pentafluoro-ethyl, 1,1-difluoro-ethyl or 2,2-difluoroethyl.

In certain embodiments of formula I, R² is phenyl substituted once or twice independently with halo or methyl.

In many embodiments of formula I, R² is phenyl substituted at the 4-position with methyl or halo and optionally substituted at the 2- and 6-positions with halo.

In many embodiments of formula I, R² is phenyl substituted at the 4-position with methyl or halo and optionally substituted at the 2-position with halo.

In certain embodiments of formula I, R² is 4-methyl-phenyl, 2-fluoro-4-methyl-phenyl, 2-chloro-4-fluoro-phenyl, 4-chloro-2-fluoro-phenyl, 2,4-dichloro-phenyl, 2,4-difluoro-phenyl, or 2-chloro-4-methyl-phenyl.

In certain embodiments of formula I, R² is 4-methyl-phenyl or 4-chloro-phenyl.

In certain embodiments of formula I, R² is 4-methyl-phenyl.

In certain embodiments of formula I, R² is 2-fluoro-4-methyl-phenyl.

In certain embodiments of formula I, R² is 2-chloro-4-fluoro-phenyl.

In certain embodiments of formula I, R² is 4-chloro-2-fluoro-phenyl.

In certain embodiments of formula I, R² is 2,4-dichloro-phenyl.

In certain embodiments of formula I, R² is 2,4-difluoro-phenyl.

In certain embodiments of formula I, R² is 2-chloro-4-methyl-phenyl.

In many embodiments of formula I, R² is optionally substituted pyridinyl. Exemplary pyridinyl include pyridin-2-yl, and pyridin-2-one-1-yl, each optionally substituted once, twice of three times with any of C₁₋₆alkyl, C₁₋₆alkyloxy, halo, C₁₋₆haloalkyl, hetero-C₁₋₆alkyl, C₁₋₆alkylsulfonyl or cyano. Preferred pyridyl include 4-methyl-pyridin-2-yl, 4-fluoro-pyridin-2-yl and 4-methyl-pyridin-2-one-1-yl.

In certain embodiments of formula I, R² is pyridin 2-yl substituted with methyl or halo at the 5-position.

In certain embodiments of formula I, R² is pyridin 2-yl substituted with methyl or halo at the 5-position and optionally substituted with halo at the 3-position.

In certain embodiments of formula I, R² is 5-methyl-pyridin-2-yl, 5-chloro-pyridin-2-yl, 5-fluoro-pyridin-2-yl, 5-methyl-3-fluoro-pyridin-2-yl, 5-methyl-3-chloro-pyridin-2-yl, 3,5-difluoro-pyridin-2-yl or 3,5-dichloro-ppyridin-2-yl.

In certain embodiments of formula I, R² is 5-methyl-pyridin-2-yl.

In certain embodiments of formula I, R² is 5-chloro-pyridin-2-yl.

In certain embodiments of formula I, R² is 5-fluoro-pyridin-2-yl.

In certain embodiments of formula I, R² is 5-methyl-3-fluoro-pyridin-2-yl.

In certain embodiments of formula I, R² is 5-methyl-3-chloro-pyridin-2-yl.

In certain embodiments of formula I, R² is 3,5-difluoro-pyridin-2-yl.

In certain embodiments of formula I, R² is 3,5-dichloro-pyridin-2-yl.

In certain embodiments of formula I, R² is optionally substituted pyridazinyl. In such embodiments R² may be 6-chloro-pyridazinyl or 6-methyl-pyridazinyl, preferably 6-chloro-pyridazinyl.

In certain embodiments of formula I, R² is optionally substituted thiophenyl. In such embodiments R² may be thiophen-2-yl optionally substituted with C₁₋₆alkyl or halo.

Preferred thiophenyl include 3-methyl-thiophen-2-yl, 5-methyl-thiophen-2-yl and 5-chloro-thiophen-2-yl.

In many embodiments of formula I, R⁶ is hydrogen. In certain embodiments of formula I, R⁶ may be methyl.

In many embodiments of formula I, R³ is hydrogen.

In certain embodiments of formula I, R⁴ is hydrogen.

In many embodiments of formula I, R³ is C₁₋₆alkyl. A preferred C₁₋₆alkyl in such embodiments is methyl.

In many embodiments of formula I, R⁴ is C₁₋₆alkyl. A preferred C₁₋₆alkyl in such embodiments is methyl.

In many embodiments of formula I, R³ is hydrogen and R⁴ is C₁₋₆alkyl, preferably methyl.

In certain embodiments of formula I, R³ and R⁴ are hydrogen.

In certain embodiments of formula I, R³ and R⁴ together with the atom to which they are attached may form a C₃₋₆ carbocyclic ring.

In certain embodiments of formula I, R³ and R⁴ together with the atom to which they are attached may form a cyclopropyl group.

In certain embodiments of formula I, R⁴ and R⁵ together with the atom to which they are attached form a C₃₋₆ carbocyclic ring that is optionally substituted with hydroxy.

In certain embodiments of formula I, R⁴ and R⁵ together with the atom to which they are attached form a cyclopropyl group.

In certain embodiments of formula I, R³ is hydrogen and R⁴ and R⁵ together with the atom to which they are attached form a cyclopropyl group.

In certain embodiments of formula I, R³ is hydrogen and R⁴ and R⁵ together with the atom to which they are attached form a cyclopentyl group optionally substituted with hydroxy.

In certain embodiments of formula I, R⁴ and R⁵ together with the atom to which they are attached form a C₄₋₆ heterocyclic ring containing one or two heteroatoms each independently selected from O, N and S.

In certain embodiments of formula I, R⁴ and R⁵ together with the atom to which they are attached form a piperidinyl group or oxetanyl ring group.

In certain embodiments of formula I, R⁴ and R⁵ together with the atom to which they are attached form a piperidin-3-yl group or an oxetan-3-yl group.

In certain embodiments of formula I, R³, R⁴ and R⁵ together with the atom to which they are attached form a six-membered heteroaryl containing one or two nitrogen atoms, and which is optionally substituted with halo, amino or C₁₋₆alkyl.

In certain embodiments of formula I, R³, R⁴ and R⁵ together with the atom to which they are attached form a heteroaryl selected from 2-oxo-1,2-dihydro-pyrimidinyl, pyridinyl, pyrimidinyl, pyridazinyl or pyridazinyl, each optionally substituted with methyl or amino.

In certain embodiments of formula I, R³, R⁴ and R⁵ together with the atom to which they are attached form a heteroaryl selected from 2-oxo-1,2-dihydro-pyrimidin-4-yl, 2-oxo-1,2-dihydro-pyrimidin-4-yl, 1-methyl-2-oxo-1,2-dihydro-pyrimidin-4-yl, 6-methyl-pyridin-3-yl, pyridazin-4-yl, 6-amino-pyridin-2-yl, 2-aminopyrimidin-4-yl or 2-amino-pyrimidin-3-yl.

In certain embodiments of formula I, R⁵ is: C₁₋₆alkyl; C₁₋₆alkyloxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; C₁₋₆alkylsulfanyl-C₁₋₆alkyl; C₁₋₆alkylsulfonyl-C₁₋₆alkyl; amino-C₁₋₆alkyl; N-C₁₋₆alkyl-amino-C₁₋₆alkyl; N,N-di-C₁₋₆alkyl-amino-C₁₋₆alkyl; C₃₋₇cycloalkyl; optionally substituted phenyl; heteroaryl, or heterocyclyl-C₁₋₆alkyl.

In certain embodiments of formula I, R⁵ is N-C₁₋₆alkyl-amino-C₁₋₆alkyl substituted with halo.

In certain embodiments of formula I, R⁵ is: C₁₋₆alkyloxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; heteroaryl, or heterocyclyl-C₁₋₆alkyl.

In certain embodiments of formula I, R⁵ is C₁₋₆alkyloxy-C₁₋₆alkyl. One preferred C₁₋₆alkyloxy-C₁₋₆alkyl is methoxymethyl.

In certain embodiments of formula I, R⁵ is hydroxy-C₁₋₆alkyl. One preferred hydroxy-C₁₋₆alkyl is hydroxymethyl.

In certain embodiments of formula I, R⁵ is heteroaryl.

In certain embodiments where R⁵ is heteroaryl, such heteroaryl may be pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, 3-oxo-2,3-dihydro-isoxazolyl, tetrazolyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, and benzimidazolyl, each of which may be optionally substituted one, two or three times with a group or groups independently selected from C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxy-C₁₋₆alkyl, halo-C₁₋₆alkyl, halo, amino, N-C₁₋₆alkyl-amino, or N,N-di-(C₁₋₆alkyl)-amino. More preferably, such heteroarly may be optionally substituted once or twice with a group or groups independently selected from methyl, ethyl, n-propyl, fluoro, chloro, trifluoromethyl, amino, methylamino or dimethylamino.

In certain embodiments where R⁵ is heteroaryl, such heteroaryl may be pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl or thiazolyl, each of which may be optionally substituted once or twice with a group or groups independently selected from methyl, ethyl, n-propyl, fluoro, chloro, amino, methylamino or dimethylamino.

In certain embodiments where R⁵ heteroaryl, such heteroaryl may be pyridinyl, pyrimidinyl, or pyrazinyl, each of which may be optionally substituted once or twice with a group or groups independently selected from methyl, fluoro, chloro, amino, methylamino or dimethylamino.

In certain embodiments of formula I, where R⁵ is heteroaryl, such heteroaryl may be thiophen-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, oxazol-2-yl, pyrimidin-2-yl, pyridazin-4-yl, pyrazin-2-yl, 5-methyl-pyrazin-2-yl, imidazol-1-yl, pyrazol-1-yl, 3,5-dimethyl-pyrazol-1-yl, 2-methyl-thiazol-4-yl, 3-(2-chloro-phenyl)-[1,2,4]-oxadiazol-5-yl, 3-(pyridin-4-yl)-[1,2,4]-oxadiazol-5-yl, pyridazin-3-yl, 2-methyl-pyrazol-3-yl, thiazol-5-yl, 1-methyl-imidazol-2-yl, 6-chloro-pyrimidin-4-yl, 4-ethyl-[1,2,4]-triazol-3-yl, 1,3,5-trimethyl-pyrazol-4-yl, 1,5-dimethyl-pyrazol-4-yl, 1,3-dimethyl-pyrazol-4-yl, 3-(2-methoxy-ethyl)[1,2,4]-oxadiazol-5-yl, 3-(pyridin-3-yl-[1,2,4]-oxadiazol-5-yl, tetrazol-5-yl, pyrazol-3-yl, 4-amino-2-methyl-pyrimidin-5-yl, 2-amino-pyrimidin-4-yl, 6-methoxy-pyridazin-3-yl, 3-oxo-2,3-dihydro-isoxazol-5-yl, 3-methyl-thiophen-2-yl, 5-methyl-[1,3,4]-oxadiazol-2-yl, 4-methyl-isoxazol-3-yl, 3-trifluoromethyl-pyrazol-1-yl, 1-methyl-pyrazol-3-yl, 3-methyl-pyrazol-1-yl, 5-methyl-3-trifluoromethyl-pyrazol-1-yl, 5-cyclopropyl-3-trifluoromethyl-pyrazol-1-yl, imidazo[2,1-b]-thiazol-6-yl, thiazol-4-yl, 2-propyl-pyrazol-3-yl, 2-ethyl-pyrazol-3-yl, 5-amino-pyridazin-2-yl, 3-amino-pyridazin-2-yl, 3-chloro-pyridazin-2-yl, 2-amino-pyrimidin-5-yl, 1-methyl-imidazol-4-yl, 6-amino-pyridin-3-yl, 6-amino-pyridazin-2-yl, 2-amino-pyridin-4-yl, 2-dimethylamino-pyrimidin-5-yl, 6-amino-pyridin-2-yl, 2-methylamino-pyridin-4-yl, 2-dimethylamino-pyridin4-yl, 3-methyl-2-dimethylamino-pyridin-4-yl, pyrimidin-5-yl, 2-methyl-pyridin-4-yl, 6-methylamino-pyridin-3-yl, 6-dimethylamino-pyridin-3-yl, 6-methylamino-pyrimidin-4-yl, 6-dimethylamino-pyridin-3-yl, 6-methylamino-pyridin-3-yl, 2-methylamino-pyrimidin-5-yl, 6-methyl-pyridin-3-yl, 4-methyl-thiazol-2-yl, 2,6-dimethyl-pyridin-3-yl, imidazo[1,2-a]pyridin-2-yl, 6-methyl-pyridin-2-yl, 1-ethyl-pyrazol-3-yl, 3-methyl-pyridin-2-yl, 4-methyl-thiazol-5-yl, 1-ethyl-imidazol-2-yl, 1-methyl-pyrazol-4-yl, imidazo[4,5-b]pyridin-2-yl, 3,5-difluoro-pyridin-2-yl, 6-fluoro-pyridin-2-yl, 1,5-dimethyl-pyrazol-3-yl, 5-methyl-pyridin-2-yl, 6-trifluoromethyl-pyridin-3-yl, 5-methyl-isoxazol-3-yl, 5-methyl-imidazol-2-yl, 5-methoxy-benzimidazol-2-yl, [1,2,4]triazol-3-yl, and 8-methyl-imidazo[1,2-a]pyridin-2-yl.

In certain embodiments of formula I, R⁵ is heterocyclyl-C₁₋₆alkyl.

In embodiments where R⁵ is heterocyclyl-C₁₋₆alkyl, such heterocyclyl-C₁₋₆alkyl may be heterocyclyl-methyl such as morpholinomethyl, piperidinyl-methyl, piperazinyl-methyl, thiomorpholinylmethyl, pyrrolidinylmethyl, or azetidinylmethyl, the heterocyclyl portion of each of which may be optionally substituted once or twice with a group or groups independently selected from methyl, methoxy, halo, methanesulfonyl, oxo or acetyl.

In embodiments where R⁵ is heterocyclyl-methyl, such heterocyclylmethyl may be morpholin-4-yl-methyl, 4-methanesulfonyl-piperazin-1-yl-methyl, 4-acetyl-piperazin-1-yl-methyl, piperidin-1-yl, thiomorpholin-4-yl-methyl, 4-methyl-piperazin-1-yl-methyl, 3-oxo-piperazin-1-yl-methyl, 3-methoxy-piperidin-1-yl-methyl, 4-methoxy-piperidin-1-yl-methyl, 4-hydroxy-piperidin-1-yl-methyl, 1-oxo-thiomorpholin-4-yl-methyl, 3-hydroxy-pyrrolidin-1-yl-methyl, azetidin-3-yl-methyl, 4-methanesulfonyl-piperidin-1-yl-methyl, 4-fluoro-piperidin-1-yl-methyl, 4-acetyl-3-methyl-piperazin-1-yl-methyl, 4-acetyl-3,5-dimethyl-piperazin-1-yl-methyl, 2,6-dimethyl-morpholin-4-yl-methyl, 4, 4-difluoro-piperidin-1-yl-methyl, 3-fluoro-piperidin-1-yl-methyl, 4-methyl-4-hydroxy-piperidin-1-yl-methyl, or 3-fluoro-4-methoxy-piperidin-1-yl-methyl.

In certain embodiments of formula I, R⁵ is hydroxymethyl, methoxymethyl, pyrazin-2-yl or 5-methyl-pyrazin-2-yl.

In certain embodiments of formula I, R⁵ is hydroxymethyl, methoxymethyl, pyrazin-2-yl, 5-methyl-pyrazin-2-yl, 6-methyl-pyridazin-3-yl, or 1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl.

In certain embodiments of formula I, R⁵ is hydroxymethyl.

In certain embodiments of formula I, R⁵ is methoxymethyl.

In certain embodiments of formula I, R⁵ is pyrazin-2-yl.

In certain embodiments of formula I, R⁵ is 5-methyl-pyrazin-2-yl.

In certain embodiments of formula I, R⁵ is 1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl.

In certain embodiments of formula I, R⁵ is 6-methyl-pyridazin-3-yl.

In certain embodiments of formula I, R⁶, R⁷ and R⁸ are hydrogen.

In certain embodiments of formula I, R⁷ and R⁸ are hydrogen.

In certain embodiments of formula I, one of R⁷ and R⁸ is halo or C₁₋₄alkoxy and the other is hydrogen.

In certain embodiments of formula I, R⁷ and R⁸ each independently is halo or C₁₋₄alkoxy.

In certain embodiments of formula I, one of R⁷ and R⁸ is fluoro, chloro or methoxy, and the other is hydrogen.

In certain embodiments of formula I, R⁷ and R⁸ each independently is fluoro, chloro or methoxy.

In certain embodiments of formula I, one of R⁷ and R⁸ is fluoro and the other is hydrogen.

In certain embodiments of formula I, one of R⁷ and R⁸ is chloro and the other is hydrogen.

In certain embodiments of formula I, one of R⁷ and R⁸ is methoxy and the other is hydrogen.

In certain embodiments of formula I, R⁷ and R⁸ are fluoro.

In certain embodiments of formula I:

R¹ is pyrazol-3-yl substituted at the 2-position with C₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, C₁₋₆alkylamino-C₁₋₆alkyl, N,N-di-(C₁₋₆alkyl)-amino-C₁₋₆alkyl, C₃₋₆-cycloalkyl, or C₃₋₆cycloalkyl-C₁₋₆alkyl;

R² is: 4-methyl-phenyl; 2-fluoro-4-methyl-phenyl; 2-chloro-4-fluoro-phenyl; 4-chloro-2-fluoro-phenyl; 2,4-dichloro-phenyl; 2,4-difluoro-phenyl;or 2-chloro-4-methyl-phenyl;

R³ is hydrogen;

R⁴ is: hydrogen; or methyl; and

R⁵ is: C₁₋₆alkyl; C₁₋₆alkyloxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; C₁₋₆alkylsulfanyl-C₁₋₆alkyl; C₁₋₆alkylsulfonyl-C₁₋₆alkyl; amino-C₁₋₆alkyl; N-C₁₋₆alkyl-amino-C₁₋₆alkyl; N,N-di-C₁₋₆alkyl-amino-C₁₋₆alkyl; C₃₋₇cycloalkyl; optionally substituted phenyl; heteroaryl, or heterocyclyl-C₁₋₆alkyl.

In certain embodiments of formula I:

R¹ is pyrazol-3-yl substituted at the 2-position with C₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, C₁₋₆alkylamino-C₁₋₆alkyl, N,N-di-(C₁₋₆alkyl)-amino-C₁₋₆alkyl, C₃₋₆-cycloalkyl, or C₃₋₆cycloalkyl-C₁₋₆alkyl;

R² is: 5-methyl-pyridin-2-yl, 5-chloro-pyridin-2-yl, 5-fluoro-pyridin-2-yl, 5-methyl-3-fluoro-pyridin-2-yl, 5-methyl-3-chloro-pyridin-2-yl, 3,5-difluoro-pyridin-2-yl or 3,5-dichloro-ppyridin-2-yl;

R³ is hydrogen;

R⁴ is: hydrogen; or methyl; and

R⁵ is: C₁₋₆alkyl; C₁₋₆alkyloxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; C₁₋₆alkylsulfanyl-C₁₋₆alkyl; C₁₋₆alkylsulfonyl-C₁₋₆alkyl; amino-C₁₋₆alkyl; N-C₁₋₆alkyl-amino-C₁₋₆alkyl; N,N-di-C₁₋₆alkyl-amino-C₁₋₆alkyl; C₃₋₇cycloalkyl; optionally substituted phenyl; heteroaryl, or heterocyclyl-C₁₋₆alkyl.

In certain embodiments of formula I:

R¹ is pyrazol-3-yl substituted at the 2-position with C₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, C₃₋₆-cycloalkyl, or C₃₋₆cycloalkyl-C₁₋₆alkyl;

R² is: 4-methyl-phenyl; 2-fluoro-4-methyl-phenyl; 2-chloro-4-fluoro-phenyl; 4-chloro-2-fluoro-phenyl; 2,4-dichloro-phenyl; 2,4-difluoro-phenyl;or 2-chloro-4-methyl-phenyl;

R³ is hydrogen;

R⁴ is: hydrogen; or methyl; and

R⁵ is: hydroxymethyl; methoxymethyl; morpholin-4-ylmethyl; piperidin-1-yl methyl optionally substituted at the 4-position with methyl, methanesulfonyl or acetyl; 1,1,-dioxo-thiomorpholin-1-yl; piperidin-1-yl-methyl optionally substituted once or twice with a group or groups selected independently from methyl, methoxy or halo; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; pyrazolyl; or thiazolyl; wherein the pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl and thiazolyl each may be optionally substituted once or twice with a group or groups selected independently from methyl, methylamino, dimethylamino and halo.

In certain embodiments of formula I:

R¹ is pyrazol-3-yl substituted at the 2-position with C₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, C₁₋₆alkylamino-C₁₋₆alkyl, C₃₋₆-cycloalkyl, or C₃₋₆cycloalkyl-C₁₋₆alkyl;

R² is: 5-methyl-pyridin-2-yl, 5-chloro-pyridin-2-yl, 5-fluoro-pyridin-2-yl, 5-methyl-3-fluoro-pyridin-2-yl, 5-methyl-3-chloro-pyridin-2-yl, 3,5-difluoro-pyridin-2-yl or 3,5-dichloro-ppyridin-2-yl;

R³ is hydrogen;

R⁴ is: hydrogen; or methyl; and

R⁵ is: hydroxymethyl; methoxymethyl; morpholin-4-ylmethyl; piperidin-1-yl methyl optionally substituted at the 4-position with methyl, methanesulfonyl or acetyl; 1,1,-dioxo-thiomorpholin-1-yl; piperidin-1-yl optionally substituted once or twice with a group or groups selected independently from methyl, methoxy or halo; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; pyrazolyl; or thiazolyl; wherein the pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl and thiazolyl each may be optionally substituted once or twice with a group or groups selected independently from methyl, methylamino, dimethylamino and halo.

In certain embodiments of formula I:

R¹ is pyrazol-3-yl substituted at the 2-position with C₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, C₃₋₆-cycloalkyl, or C₃₋₆cycloalkyl-C₁₋₆alkyl;

R² is: 4-methyl-phenyl; 2-fluoro-4-methyl-phenyl; 2-chloro-4-fluoro-phenyl; 4-chloro-2-fluoro-phenyl; 2,4-dichloro-phenyl; 2,4-difluoro-phenyl;or 2-chloro-4-methyl-phenyl;

R³ is hydrogen; and

R⁴ and R⁵ together form a cyclopropyl group.

In certain embodiments of formula I:

R¹ is pyrazol-3-yl substituted at the 2-position with C₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, C₁₋₆alkylamino-C₁₋₆alkyl, C₃₋₆-cycloalkyl, or C₃₋₆cycloalkyl-C₁₋₆alkyl;

R² is: 5-methyl-pyridin-2-yl, 5-chloro-pyridin-2-yl, 5-fluoro-pyridin-2-yl, 5-methyl-3-fluoro-pyridin-2-yl, 5-methyl-3-chloro-pyridin-2-yl, 3,5-difluoro-pyridin-2-yl or 3,5-dichloro-ppyridin-2-yl;

R³ is hydrogen; and

R⁴ and R⁵ together form a cyclopropyl group.

In certain embodiments of formula I:

R¹ is pyrazol-3-yl substituted at the 2-position with C₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, C₁₋₆alkylamino-C₁₋₆alkyl, N,N-di-(C₁₋₆alkyl)-amino-C₁₋₆alkyl, C₃₋₆-cycloalkyl, or C₃₋₆cycloalkyl-C₁₋₆alkyl;

R² is: 4-methyl-phenyl; 2-fluoro-4-methyl-phenyl; 2-chloro-4-fluoro-phenyl; 4-chloro-2-fluoro-phenyl; 2,4-dichloro-phenyl; 2,4-difluoro-phenyl;or 2-chloro-4-methyl-phenyl;

R³ is hydrogen;

R⁴ is methyl; and

R⁵ is methoxymethyl, hydroxymethyl, 5-methyl-pyrazin-2-yl or pyrazin-2-yl.

In certain embodiments of formula I:

R¹ is pyrazol-3-yl substituted at the 2-position with C₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, C₁₋₆alkylamino-C₁₋₆alkyl, N,N-di-(C₁₋₆alkyl)-amino-C₁₋₆alkyl, C₃₋₆-cycloalkyl, or C₃₋₆cycloalkyl-C₁₋₆alkyl;

R² is: 5-methyl-pyridin-2-yl, 5-chloro-pyridin-2-yl, 5-fluoro-pyridin-2-yl, 5-methyl-3-fluoro-pyridin-2-yl, 5-methyl-3-chloro-pyridin-2-yl, 3,5-difluoro-pyridin-2-yl or 3,5-dichloro-ppyridin-2-yl;

R³ is hydrogen;

R⁴ is methyl; and

R⁵ is methoxymethyl, hydroxymethyl, 5-methyl-pyrazin-2-yl or pyrazin-2-yl.

In certain embodiments of formula I:

R¹ is pyrazol-3-yl substituted at the 2-position with C₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, C₁₋₆alkylamino-C₁₋₆alkyl, N,N-di-(C₁₋₆alkyl)-amino-C₁₋₆alkyl, C₃₋₆-cycloalkyl, or C₃₋₆cycloalkyl-C₁₋₆alkyl;

R² is: 4-methyl-phenyl; 2-fluoro-4-methyl-phenyl; 2-chloro-4-fluoro-phenyl; 4-chloro-2-fluoro-phenyl; 2,4-dichloro-phenyl; 2,4-difluoro-phenyl;or 2-chloro-4-methyl-phenyl;

R³ and R⁴ are hydrogen; and

R⁵ is 5-methyl-pyrazin-2-yl.

In certain embodiments of formula I:

R¹ is pyrazol-3-yl optionally substituted at the 2-position with C₁₋₆alkyl, halo-C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, C₁₋₆alkylamino-C₁₋₆alkyl, N,N-di-(C₁₋₆alkyl)-amino-C₁₋₆alkyl, C₃₋₆-cycloalkyl, or C₃₋₆cycloalkyl-C₁₋₆alkyl;

R² is: 5-methyl-pyridin-2-yl, 5-chloro-pyridin-2-yl, 5-fluoro-pyridin-2-yl, 5-methyl-3-fluoro-pyridin-2-yl, 5-methyl-3-chloro-pyridin-2-yl, 3,5-difluoro-pyridin-2-yl or 3,5-dichloro-ppyridin-2-yl;

R³ and R⁴ are hydrogen; and

R⁵ is 5-methyl-pyridazin-2-yl.

In formula I, R¹ may be represented by a group of formula A;

wherein R^(a) and R^(b) each independently is: hydrogen; C₁₋₆alkyl; C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; phenyl; amino; N—C₁₋₆alkyl-amino; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; hetero-C₁₋₆alkyl; C₃₋₆-cycloalkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl; aminocarbonyl; heterocyclylcarbonyl; C₁₋₆alkoxycarbonyl; or cyano; or R^(a) and R^(b) together with the atoms to which they are attached may form a phenyl, pyridinyl or pyrimidinyl group, each optionally substituted; and wherein R^(c) is hydrogen, C₁₋₆alkyl or halo-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is a group of formula A1:

wherein R^(a), R^(b) and R^(c) are as defined herein.

In certain embodiments of formula I, R¹ is a group of formula A2:

wherein R^(a), R^(b) and R^(c) are as defined herein.

In certain embodiments of formula I, R¹ is a group of formula A3:

wherein R^(a), R^(b) and R^(c) are as defined herein.

In certain embodiments of formula I, R^(a) and R^(c) are hydrogen and R^(b) is: hydrogen; C₁₋₆alkyl; C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; amino; N—C₁₋₆alkyl-amino; N,N-di-C₁₋₆alkyl-amino halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; hetero-C₁₋₆alkyl; C₃₋₆-cycloalkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl; aminocarbonyl; heterocyclylcarbonyl; C₁₋₆alkoxycarbonyl; or cyano.

In embodiments of formula I wherein R^(a) or R^(b) is hetero-C₁₋₆alkyl , such hetero-C₁₋₆alkyl may be selected from hydroxy-C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl, C₁₋₆alkylamino-C₁₋₆alkyl, and N,N-di-(C₁₋₆alkyl)-amino-C₁₋₆alkyl.

In certain embodiments of formula I, R^(a) and R^(c) are hydrogen and R^(b) is methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, phenyl, trifluoromethyl, difluoromethyl, fluoromethyl, pentafluoro-ethyl, 1,1-difluoro-ethyl, 2,2-difluoroethyl, 1-methoxy-ethyl, 1-ethoxy-ethyl, 2-methoxy-1-methyl-ethyl, 1-hydroxy-ethyl, isopropoxy, 1-methyl-azetidin-2-yl, 1-dimethylamino-ethyl or dimethylamino-methyl.

In certain embodiments of formula I, R^(a), R^(b) and R^(c) each independently is hydrogen, C₁₋₆alkyl or halo-C₁₋₆alkyl.

In certain embodiments of formula I, R^(a), R^(b) and R^(c) each independently is hydrogen or C₁₋₆alkyl.

In certain embodiments of formula I, R^(a) and R^(c) are hydrogen and R^(b) is C₁₋₆alkyl or halo-C₁₋₆alkyl.

In certain embodiments of formula I, R^(a) and R^(c) are hydrogen and R^(b) is C₁₋₆alkyl.

In certain embodiments of formula I, R^(a) and R^(c) are hydrogen and R^(b) is C₁₋₆alkoxy.

In certain embodiments of formula I, R^(a) and R^(c) are hydrogen and R^(b) is C₁₋₆alkylsulfonyl.

In certain embodiments of formula I, R^(a) and R^(c) are hydrogen and R^(b) is amino.

In certain embodiments of formula I, R^(a) and R^(c) are hydrogen and R^(b) is N—C₁₋₆alkyl-amino.

In certain embodiments of formula I, R^(a) and R^(c) are hydrogen and R^(b) is N,N-di-C₁₋₆alkyl-amino.

In certain embodiments of formula I, R^(a) and R^(c) are hydrogen and R^(b) is halo-C₁₋₆alkyl.

In certain embodiments of formula I, R^(a) and R^(c) are hydrogen and R^(b) is halo-C₁₋₆alkoxy.

In certain embodiments of formula I, R^(a) and R^(c) are hydrogen and R^(b) is hetero-C₁₋₆alkyl.

In certain embodiments of formula I, R^(a) and R^(c) are hydrogen and R^(b) is C₃₋₆-cycloalkyl.

In certain embodiments of formula I, R^(a) and R^(c) are hydrogen and R^(b) is C₃₋₆cycloalkyl-C₁₋₆alkyl.

In certain embodiments of formula I, R^(a) and R^(c) are hydrogen and R^(b) is aminocarbonyl.

In certain embodiments of formula I, R^(a) and R^(c) are hydrogen and R^(b) is heterocyclylcarbonyl.

In certain embodiments of formula I, R^(a) and R^(c) are hydrogen and R^(b) is C₁₋₆alkoxycarbonyl.

In certain embodiments of formula I, R^(a) and R^(c) are hydrogen and R^(b) is cyano.

In certain embodiments of formula I, R^(a) and R^(c) are hydrogen and R^(b) is methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclopropylmethyl, trifluoromethyl, pentafluoro-ethyl, 1,1-difluoro-ethyl, 1-methoxy-ethyl, 1-ethoxy-ethyl, 2-methoxy-1-methyl-ethyl, 1-hydroxy-ethyl, or dimethylamino-methyl.

In certain embodiments of formula I, R^(a) and R^(c) are hydrogen and R^(b) is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl or cyclopropylmethyl.

In certain embodiments of formula I, R^(a) and R^(b) together with the atoms to which they are attached form optionally substituted phenyl.

In certain embodiments of formula I, R^(a) and R^(b) together with the atoms to which they are attached form optionally substituted pyridinyl.

In certain embodiments of formula I, R^(a) and R^(b) together with the atoms to which they are attached form optionally substituted pyrimidinyl.

“Optionally substituted pyrazolyl” as used herein includes pyrazolyl that optionally have a fused 6-membered aromatic or nitrogen-containing heteroaryl ring thereon. Thus, “optionally substituted pyrazole” includes indazolyl and pyrazolo[1,5-a]pyridinyl, as well as aza-substituted derivatives thereof. Accordingly, in certain embodiments of formula I where R^(a) and R^(b) together with the atoms to which they are attached form optionally substituted phenyl, R¹ may be a group of formula A4

wherein R^(c) and R^(d) each independently is hydrogen, alkyl, halo, haloalkyl, alkoxy, cyano, amino or alkylsulfonyl.

In many embodiments of formula I, R³ is hydrogen and R⁴ is C₁₋₆alkyl, preferably methyl.

In certain embodiments of formula I, R² is 4-methyl-phenyl, 4-chloro-phenyl or 2-fluoro-4-methyl-phenyl, and R³ is hydrogen.

In certain embodiments of formula I, R² is 4-methyl-phenyl, 4-chloro-phenyl or 2-fluoro-4-methyl-phenyl, R³ is hydrogen, and R⁴ is methyl.

In certain embodiments of formula I, R² is 4-methyl-phenyl, 4-chloro-phenyl or 2-fluoro-4-methyl-phenyl, R³ is hydrogen, R⁴ is methyl, and R⁶ is hydrogen.

In certain embodiments of formula I, R² is 4-methyl-phenyl, R³ is hydrogen, R⁴ is methyl, R⁶ is hydrogen, and R⁵ is:

C₁₋₆alkyl selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and isopentyl;

hetero-C₁₋₆alkyl selected from C₁₋₆alkyloxy-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, C₁₋₆alkylsulfanyl-C₁₋₆alkyl, C₁₋₆alkyl-sulfinyl-C₁₋₆alkyl, C₁₋₆alkyl-sulfonyl-C₁₋₆alkyl, amino-C₁₋₆alkyl, N-C₁₋₆alkylamino-C₁₋₆alkyl, N,N-di-C₁₋₆alkylamino-C₁₋₆alkyl and hydroxy-C₁₋₆alkyloxy;

C₃₋₇cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each optionally substituted;

aryl selected from optionally substituted phenyl and optionally substituted naphthyl;

heteroaryl selected from pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, isoxazolyl and isothiazolyl, each optionally substituted;

heterocyclyl selected from piperdinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, pyranyl, pyrrolidinyl, tetrahydrofuranyl, 2-oxa-8-aza-spiro[4.5]decan-8-yl, 2-oxa-5-aza-bicyclo[2.2.1]heptan-5-yl, and 3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl, each optionally substituted;

C₃₋₇cycloalkyl-C₁₋₆alkyl selected from cyclopropyl-C₁₋₆alkyl, cyclobutyl-C₁₋₆alkyl, cyclopentyl-C₁₋₆alkyl and cyclohexyl-C₁₋₆alkyl, the cycloalkyl portion of each being optionally substituted;

aryl-C₁₋₆alkyl selected from phenyl-C₁₋₆alkyl and naphthyl-C₁₋₆alkyl, the aryl portion of each being optionally substituted;

heteroaryl-C₁₋₆alkyl selected from pyridinyl-C₁₋₆alkyl, pyrimidinyl-C₁₋₆alkyl, pyridazinyl-C₁₋₆alkyl, pyrazinyl-C₁₋₆alkyl, furanyl-C₁₋₆alkyl, thienyl-C₁₋₆alkyl, pyrrolyl-C₁₋₆alkyl, oxazolyl-C₁₋₆alkyl, thiazolyl-C₁₋₆alkyl, imidazolyl-C₁₋₆alkyl, isoxazolyl-C₁₋₆alkyl and isothiazolyl-C₁₋₆alkyl, the heteroaryl portion of each being optionally substituted;

heterocyclyl-C₁₋₆alkyl selected from piperdinyl-C₁₋₆alkyl, piperazinyl-C₁₋₆alkyl, morpholinyl-C₁₋₆alkyl, thiomorpholinyl-C₁₋₆alkyl, 1-oxo-thiomorpholinyl-C₁₋₆alkyl, 1,1-dioxo-thiomorpholinyl-C₁₋₆alkyl, pyranyl-C₁₋₆alkyl, pyrrolidinyl-C₁₋₆alkyl, tetrahydrofuranyl-C₁₋₆alkyl, 2-oxa-8-aza-spiro[4.5]decan-8-yl-C₁₋₆alkyl, 2-oxa-5-aza-bicyclo[2.2.1]heptan-5-yl-C₁₋₆alkyl, 3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl-C₁₋₆alkyl, the heterocyclyl portion of each being optionally substituted;

aryloxy-C₁₋₆alkyl selected from phenoxy-C₁₋₆alkyl and naphthyloxy-C₁₋₆alkyl, the aryl portion of each being optionally substituted; or

—C(O)—R⁸ or —CH₂—C(O)—R⁸ wherein R⁸ is as defined herein.

In certain embodiments of formula I, R² is 4-methyl-phenyl, 4-chloro-phenyl or 2-fluoro-4-methyl-phenyl, R³ is hydrogen, R⁴ is methyl, R⁶ is hydrogen, and R⁵ is:

-   -   C₁₋₆alkoxy-C₁₋₆alkyl;     -   hydroxy-C₁₋₆alkyl;     -   morpholin-4-yl-C₁₋₆alkyl;     -   pyrazinyl; or     -   piperazin-1-yl-C₁₋₆alkyl wherein the piperazinyl moiety is         optionally substituted at the 4-position with C₁₋₆alkyl,         C₁₋₆alkylcarbonyl or C₁₋₆alkylsulfonyl.

In certain embodiments of formula I, R² is 4-methyl-phenyl, 4-chloro-phenyl or 2-fluoro-4-methyl-phenyl, R³ is hydrogen, R⁴ is methyl, R⁶ is hydrogen, and R⁵ is:

methoxymethyl;

hydroxymethyl;

morpholin-4-yl-methyl;

pyrazin-2-yl; or

4-methanesulfonyl-piperazin-1-yl.

In certain embodiments of formula I, R¹ is a group of formula A, R² is 4-methyl-phenyl, 4-chloro-phenyl or 2-fluoro-4-methyl-phenyl, R³ is hydrogen, R⁴ is methyl, R⁶ is hydrogen, and R⁵ is:

-   -   C₁₋₆alkoxy-C₁₋₆alkyl;     -   hydroxy-C₁₋₆alkyl;     -   morpholin-4-yl-C₁₋₆alkyl;     -   pyrazinyl; or     -   piperazin-1-yl-C₁₋₆alkyl wherein the piperazinyl moiety is         optionally substituted at the 4-position with C₁₋₆alkyl,         C₁₋₆alkylcarbonyl or C₁₋₆alkylsulfonyl.

In certain embodiments of formula I, R¹ is a group of formula A, R² is 4-methyl-phenyl, 4-chloro-phenyl or 2-fluoro-4-methyl-phenyl, R³ is hydrogen, R⁴ is methyl, R⁶ is hydrogen, and R⁵ is:

methoxymethyl;

hydroxymethyl;

morpholin-4-yl-methyl;

pyrazin-2-yl; or

4-methanesulfonyl-piperazin-1-yl.

In certain embodiments of formula I, R² is pyridin-2-yl substituted at the 5-position with methyl or halo, and R³ is hydrogen.

In certain embodiments of formula I, R² is pyridin-2-yl substituted at the 5-position with methyl or halo, R³ is hydrogen, and R⁴ is methyl.

In certain embodiments of formula I, R² is pyridin-2-yl substituted at the 5-position with methyl or halo, R³ is hydrogen, R⁴ is methyl, and R⁶ is hydrogen.

In certain embodiments of formula I, R² is pyridin-2-yl substituted at the 5-position with methyl or halo, R³ is hydrogen, R⁴ is methyl, R⁶ is hydrogen, and R⁵ is:

C₁₋₆alkyl selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and isopentyl;

hetero-C₁₋₆alkyl selected from C₁₋₆alkyloxy-C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, C₁₋₆alkylsulfanyl-C₁₋₆alkyl, C₁₋₆alkyl-sulfinyl-C₁₋₆alkyl, C₁₋₆alkyl-sulfonyl-C₁₋₆alkyl, amino-C₁₋₆alkyl, N—C₁₋₆alkylamino-C₁₋₆alkyl, N,N-di-C₁₋₆alkylamino-C₁₋₆alkyl and hydroxy-C₁₋₆alkyloxy;

C₃₋₇cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each optionally substituted;

aryl selected from optionally substituted phenyl and optionally substituted naphthyl;

heteroaryl selected from pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, isoxazolyl and isothiazolyl, each optionally substituted;

heterocyclyl selected from piperdinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, pyranyl, pyrrolidinyl, tetrahydrofuranyl, 2-oxa-8-aza-spiro[4.5]decan-8-yl, 2-oxa-5-aza-bicyclo[2.2.1]heptan-5-yl, and 3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl, each optionally substituted;

C₃₋₇cycloalkyl-C₁₋₆alkyl selected from cyclopropyl-C₁₋₆alkyl, cyclobutyl-C₁₋₆alkyl, cyclopentyl-C₁₋₆alkyl and cyclohexyl-C₁₋₆alkyl, the cycloalkyl portion of each being optionally substituted;

aryl-C₁₋₆alkyl selected from phenyl-C₁₋₆alkyl and naphthyl-C₁₋₆alkyl, the aryl portion of each being optionally substituted;

heteroaryl-C₁₋₆alkyl selected from pyridinyl-C₁₋₆alkyl, pyrimidinyl-C₁₋₆alkyl, pyridazinyl-C₁₋₆alkyl, pyrazinyl-C₁₋₆alkyl, furanyl-C₁₋₆alkyl, thienyl-C₁₋₆alkyl, pyrrolyl-C₁₋₆alkyl, oxazolyl-C₁₋₆alkyl, thiazolyl-C₁₋₆alkyl, imidazolyl-C₁₋₆alkyl, isoxazolyl-C₁₋₆alkyl and isothiazolyl-C₁₋₆alkyl, the heteroaryl portion of each being optionally substituted;

heterocyclyl-C₁₋₆alkyl selected from piperdinyl-C₁₋₆alkyl, piperazinyl-C₁₋₆alkyl, morpholinyl-C₁₋₆alkyl, thiomorpholinyl-C₁₋₆alkyl, 1-oxo-thiomorpholinyl-C₁₋₆alkyl, 1,1-dioxo-thiomorpholinyl-C₁₋₆alkyl, pyranyl-C₁₋₆alkyl, pyrrolidinyl-C₁₋₆alkyl, tetrahydrofuranyl-C₁₋₆alkyl, 2-oxa-8-aza-spiro[4.5]decan-8-yl-C₁₋₆alkyl, 2-oxa-5-aza-bicyclo[2.2.1]heptan-5-yl-C₁₋₆alkyl, 3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl-C₁₋₆alkyl, the heterocyclyl portion of each being optionally substituted;

aryloxy-C₁₋₆alkyl selected from phenoxy-C₁₋₆alkyl and naphthyloxy-C₁₋₆alkyl, the aryl portion of each being optionally substituted; or

—C(O)—R⁸ or —CH₂—C(O)—R⁸ wherein R⁸ is as defined herein.

In certain embodiments of formula I, R² is pyridin-2-yl substituted at the 5-position with methyl or halo, R³ is hydrogen, R⁴ is methyl, R⁶ is hydrogen, and R⁵ is:

-   -   C₁₋₆alkoxy-C₁₋₆alkyl;     -   hydroxy-C₁₋₆alkyl;     -   morpholin-4-yl-C₁₋₆alkyl;     -   pyrazinyl; or     -   piperazin-1-yl-C₁₋₆alkyl wherein the piperazinyl moiety is         optionally substituted at the 4-position with C₁₋₆alkyl,         C₁₋₆alkylcarbonyl or C₁₋₆alkylsulfonyl.

In certain embodiments of formula I, R² is pyridin-2-yl substituted at the 5-position with methyl or halo, R³ is hydrogen, R⁴ is methyl, R⁶ is hydrogen, and R⁵ is:

methoxymethyl;

hydroxymethyl;

morpholin-4-yl-methyl;

pyrazin-2-yl; or

4-methanesulfonyl-piperazin-1-yl.

In certain embodiments of formula I, R¹ is a group of formula A, R² is pyridin-2-yl substituted at the 5-position with methyl or halo, R³ is hydrogen, R⁴ is methyl, R⁶ is hydrogen, and R⁵ is:

-   -   C₁₋₆alkoxy-C₁₋₆alkyl;     -   hydroxy-C₁₋₆alkyl;     -   morpholin-4-yl-C₁₋₆alkyl;     -   pyrazinyl; or     -   piperazin-1-yl-C₁₋₆alkyl wherein the piperazinyl moiety is         optionally substituted at the 4-position with C₁₋₆alkyl,         C₁₋₆alkylcarbonyl or C₁₋₆alkylsulfonyl.

In certain embodiments of formula I, R¹ is a group of formula A, R² is pyridin-2-yl substituted at the 5-position with methyl or halo, R³ is hydrogen, R⁴ is methyl, R⁶ is hydrogen, and R⁵ is:

methoxymethyl;

hydroxymethyl;

morpholin-4-yl-methyl;

pyrazin-2-yl; or

4-methanesulfonyl-piperazin-1-yl.

In certain embodiments of formula I the subject compounds are more specifically of formula II:

or a pharmaceutically acceptable salt thereof, wherein:

X is C or N;

R¹¹ and R¹² each independently is:

-   -   hydrogen;     -   C₁₋₆alkyl; C₁₋₆alkyloxy;     -   halo;     -   halo-C₁₋₆alkyl;     -   halo-C₁₋₆alkoxy;     -   hetero-C₁₋₆alkyl;     -   C₁₋₆alkylsulfonyl; or     -   cyano; and

R¹ and R⁵ are as defined herein.

In certain embodiments of formula II, the compounds of the invention are of formula IIa or IIb:

wherein X, R¹, R⁵, R¹¹ and R¹² are as defined herein.

In certain embodiments of formula I the subject compounds are more specifically of formula III:

or a pharmaceutically acceptable salt thereof, wherein X, R¹, R⁵, R¹¹ and R¹² are as defined herein.

In certain embodiments of any of formulas I, IIa, IIb, or III, R⁵ is:

wherein:

n is 0, 1 or 2;

R^(c) and R^(d) each independently is hydrogen or C₁₋₆alkyl;

R^(e) is hydrogen, C₁₋₆alkyl, acetyl or C₁₋₆alkyl-sulfonyl;

R^(f) and R^(g) each independently is hydrogen or C₁₋₆alkyl;

R^(h) and R^(i) each independently is hydrogen, C₁₋₆alkyl, fluoro, hydroxy or C₁₋₆alkyloxy;

R^(j) and R^(k) each independently is hydrogen or C₁₋₆alkyl; and

R^(m), R^(n), R^(o), R^(p), R^(q) and R^(r), each independently is hydrogen,C₁₋₆alkyl, halo, C₁₋₆alkoxy, C₁₋₆alkyl-sulfonyl halo-C₁₋₆alkyl, or cyano.

In certain embodiments of any of formulas I, IIa, IIb, or III, R⁵ is:

wherein R^(e) is as defined herein.

In certain embodiments of any of formulas I, IIa, IIb, or III, R⁵ is:

Where any of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R^(a), R^(b), R^(c), R^(d) and R^(e) is alkyl or contains an alkyl moiety, such alkyl is preferably lower alkyl, i.e. C₁-C₆alkyl, and more preferably C₁-C₄alkyl.

The invention also provides methods for treating a disease or condition mediated by or otherwise associated with a P2X₃ receptor antagonist, a P2X_(2/3) receptor antagonist, or both, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention.

The disease may be genitorurinary disease or urinary tract disease. In other instances the disease may be a disease is associated with pain. The urinary tract disease may be: reduced bladder capacity; frequent micturition; urge incontinence; stress incontinence; bladder hyperreactivity; benign prostatic hypertrophy; prostatitis; detrusor hyperreflexia; urinary frequency; nocturia; urinary urgency; overactive bladder; pelvic hypersensitivity; urethritis; prostatitits; pelvic pain syndrome; prostatodynia; cystitis; or idiophatic bladder hypersensitivity.

The disease associated with pain may be: inflammatory pain; surgical pain; visceral pain; dental pain; premenstrual pain; central pain; pain due to burns; migraine or cluster headaches; nerve injury; neuritis; neuralgias; poisoning; ischemic injury; interstitial cystitis;

cancer pain; viral, parasitic or bacterial infection; post-traumatic injury; or pain associated with irritable bowel syndrome.

The disease may be a respiratory disorder, such as chronic obstructive pulmonary disorder (COPD), asthma, or bronchospasm, or a gastrointestinal (GI) disorder such as Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, pain associated with GI distension.

Representative compounds in accordance with the methods of the invention are shown in Table 1.

TABLE 1 # Structure Name (Autonom ™) MP/M + H 1

4′-Methyl-5-(1-methyl-1H- pyrazol-4-yl)-biphenyl-3- carboxylic acid (2-methoxy-1- methylethyl)-amide 364 2

4′-Methyl-5-(1H-pyrazol-4-yl)- biphenyl-3-carboxylic acid (2- methoxy-1-methyl-ethyl)-amide 350 3

5-Indazol-1-yl-4′-methyl- biphenyl-3-carboxylic acid (2- methoxy-1-methyl-ethyl)-amide 400 4

5-Isopropyl-1-[5-(2-methoxy-1- methyl-ethylcarbamoyl)-4′- methyl-biphenyl-3-yl]-1H- pyrazole-3-carboxylic acid ethyl ester 464 5

5-Isopropyl-1-[5-(2-methoxy-1- methyl-ethylcarbamoyl)-4′- methyl-biphenyl-3-yl]-1H- pyrazol-3-carboxylic acid dimethylamide 463 6

5-Isopropyl-1-[5-(1-methoxy-1- methyl-ethylcarbamoyl)-4′- methyl-biphenyl-3-yl]-1H- pyrazole-3-carboxylic acid methylamide 449 7

5-Isopropyl-1-[5-(2-methoxy-1- methyl-ethylcarbamoyl)-4′- methyl-biphenyl-3-yl]-1H- pyrazole-3-carboxylic acid isopropylamide 477 8

1-[5-(2-Methoxy-1-methyl- ethylcarbamoyl)-4′-methyl- biphenyl-3-yl]-5-methyl-1H- pyrazole-3-carboxylic acid ethyl ester 436 9

1-[5-(2-Methoxy-1-methyl- ethylcarbamoyl)-4′-methyl- biphenyl-3-yl]-5-methyl-1H- pyrazole-3-carboxylic acid isopropylamide 449 10

1-[5-(2-Methoxy-1-methyl- ethylcarbamoyl)-4′-methyl- biphenyl-3-yl]-5-methyl-1H- pyrazole-3-carboxylic acid dimethylamide 435 11

1-[5-(2-Methoxy-1-methyl- ethylcarbamoyl)-4′-methyl- biphenyl-3-yl]-5-methyl-1H- pyrazole-3-carboxylic acid methylamide 421 12

4′-Methyl-5-(3-methyl-pyrazol- 1-yl)-biphenyl)-3-carboxylic acid (2-methoxy-1-methyl-ethyl)- amide 364 13

5-(3,5-Dimethyl-pyrazol-1-yl)- 4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl- ethyl)-amide 378 14

4′-Methyl-5-(2-methyl-2H- pyrazol-3-yl)-biphenyl-3- carboxylic acid (2-methoxy-1- methyl-ethyl)-amide 364 15

4′-Methyl-5-(1,3,5-trimethyl- 1H-pyrazol-4-yl)-biphenyl-3- carboxylic acid (2-methoxy-1- methyl-ethyl)-amide 392 16

4′-Methyl-5-(1,3,5-trimethyl- 1H-pyrazol-4-yl)-biphenyl-3- carboxylic acid (1-pyrazin-2-yl- ethyl)-amide 426 17

5-(2-Isopropyl-2H-pyrazol-3- yl)-4′-methyl-biphenyl-3- carboxylic acid (1-pyrazin-2-yl- ethyl)-amide 426 18

5-(2-Isopropyl-2H-pyrazol-3- yl)-4′-methyl-biphenyl-3- carboxylic acid (2-methoxy-1- methyl-ethyl)-amide 392 19

5-(2-Isopropyl-2H-pyrazol-3- yl)-4′-methyl-biphenyl-3- carboxylic acid (2-hydroxy-1- methyl-ethyl)-amide 378 20

5-(2-Isopropyl-2H-pyrazol-3- yl)-4′-methyl-biphenyl-3- carboxylic acid ((S)-2-hydroxy- 1-methyl-ethyl)-amide 378 21

5-(2-Isopropyl-2H-pyrazol-3- yl)-4′-methyl-biphenyl-3- carboxylic acid ((S)-2-methoxy- 1-methyl-ethyl)-amide 392 22

5-(2-Isopropyl-2H-pyrazol-3- yl)-4′-methyl-biphenyl-3- carboxylic acid ((R)-1-methyl-2- morpholin-4-yl-ethyl)-amide 447 23

5-(2-Isopropyl-2H-pyrazol-3- yl)-4′-methyl-biphenyl-3- carboxylic acid [(R)-2-(1,1- dioxo-1λ⁶-thiomorpholin-4-yl)- 1-methyl-ethyl]-amide 495 24

2′-Fluoro-5-(2-isopropyl-2H- pyrazol-3-yl)-4′-methyl- biphenyl-3-carboxylic acid (2- hydroxy-1-methyl-ethyl)-amide 396 25

3-(2-Isopropyl-2H-pyrazol-3- yl)-5-(5-methyl-pyridin-2-yl)-N- (1-pyrazin-2-yl-ethyl)- benzamide 427 26

3-(3-Chloro-5-methyl-pyridin-2- yl)-5-(2-isopropyl-2H-pyrazol- 3-yl)-N-(1-pyrazin-2-yl-ethyl)- benzamide 461 27

3-(5-Iospropyl-pyrazol-1-yl)-5- (5-methyl-pyridin-2-yl)-N-(1- pyrazin-2-yl-ethyl)-benzamide 28

N-(2-Hydorxy-1-methyl-ethyl)- 3-(5-isopropyl-pyrazol-1-yl)-5- (5-methyl-pyridin-2-yl)- benzamide 379 29

3-(2-Ethyl-2H-pyrazol-3-yl)-5- (5-methyl-pyridin-2-yl)-N-(1- pyrazin-2-yl-ethyl)-benzamide 413 30

3-(2-Ethyl-2H-pyrazol-3-yl)-N- (2-hydroxy-1-methyl-ethyl)-5- (5-methyl-pyridin-2-yl)- benzamide 365 31

N-Cyclopropyl-3-(2-isobutyl- 2H-pyrazol-3-yl)-5-(5-methyl- pyridin-2-yl)-benzamide 375 32

3-(3-Fluoro-5-methyl-pyridin-2- yl)-5-(2-isopropyl-2H-pyrazol- 3-yl)-N-(1-pyrazin-2-yl-ethyl)- benzamide 445 33

3-(3-Fluoro-5-methyl-pyridin-2- yl)-5-(2-isopropyl-2H-pyrazol- 3-yl)-N-(5-methyl-pyrazin-2- ylmethyl)-benzamide 445 34

3-(3-Fluoro-5-methyl-pyridin-2- yl)-N-((S)-2-hydroxy-1-methyl- ethyl)-5-(2-isopropyl-2H- pyrazol-3-yl)-benzamide 397 35

N-Cyclopropyl-3-(3-fluoro-5- methyl-pyridin-2-yl)-5-(2- isopropyl-2H-pyrazol-3-yl)- benzamide 379 36

3-(5-Chloro-pyridin-2-yl)-5-(2- isopropyl-2H-pyrazol-3-yl)-N- (1-pyrazin-2-yl-ethyl)- benzamide 447 37

3-(5-Chloro-pyridin-2-yl)-5-(2- isopropyl-2H-pyrazol-3-yl)-N- (5-methyl-pyrazin-2-ylmethyl)- benzamide 447 38

N-(5-Methyl-pyrazin-2- ylmethyl)-3-(5-methyl-pyridin- 2-yl)-5-(2-propyl-2H-pyrazol-3- yl)-benzamide 427 39

3-(5-Methyl-pyridin-2-yl)-5-(2- propyl-2H-pyrazol-3-yl)-N-(1- pyrazin-2-yl-ethyl)-benzamide 427 40

N-((S)-2-Hydroxy-1-methyl- ethyl)-3-(5-methyl-pyridin-2- yl)-5-(2-propyl-2H-pyrazol-3- yl)-benzamide 379 41

N-Cyclopropyl-3-(5-methyl- pyridin-2-yl)-5-(2-propyl-2H- pyrazol-3-yl)-benzamide 361 42

3-(5-Chloro-pyridin-2-yl)-5-(2- ethyl-2H-pyrazol-3-yl)-N-(5- methyl-pyrazin-2-ylmethyl)- benzamide 433 43

3-(5-Chloro-pyridin-2-yl)-5-(2- ethyl-2H-pyrazol-3-yl)-N-(1- pyrazin-2-yl-ethyl)-benzamide 433 44

3-(5-Chloro-pyridin-2-yl)-5-(2- ethyl-2H-pyrazol-3-yl)-N-((S)- 2-hydroxy-1-methyl-ethyl)- benzamide 385 45

3-(5-Chloro-pyridin-2-yl)-N- cyclopropyl-5-(2-ethyl-2H- pyrazol-3-yl)-benzamide 367 46

N-((S)-2-Hydroxy-1-methyl- ethyl)-3-(2-isopropyl-2H- pyrazol-3-yl)-5-(5-methyl- pyridin-2-yl)-benzamide 379 47

N-(5-Amino-pyrazin-2- ylmethyl)-3-(2-isopropyl-2H- pyrazol-3-yl)-5-(5-methyl- pyridin-2-yl)-benzamide 428 48

4′-Methyl-5-(2-methyl-2H- pyrazol-3-yl)-biphenyl-3- carboxylic acid (5-methyl- pyrazin-2-ylmethyl)-amide 398 49

4′-Methyl-5-(2-methyl-2H- pyrazol-3-yl)-biphenyl-3- carboxylic acid (1-pyrazin-2-yl- ethyl)-amide 398 50

4′-Methyl-5-(2-methyl-2H- pyrazol-3-yl)-biphenyl-3- carboxylic acid ((S)-2-hydroxy- 1-methyl-ethyl)-amide 350 51

N-(5-Methyl-pyrazin-2- ylmethyl)-3-(2-methyl-2H- pyrazol-3-yl)-5-(5-methyl- pyridin-2-yl)-benzamide 399 52

3-(2-Methyl-2H-pyrazol-3-yl)- 5-(5-methyl-pyridin-2-yl)-N-(1- pyrazin-2-yl-ethyl)-benzamide 399 53

N-((S)-2-Hydroxy-1-methyl- ethyl)-3-(2-methyl-2H-pyrazol- 3-yl)-5-(5-methyl-pyridin-2-yl)- benzamide 351 54

N-Cyclopropyl-3-(2-methyl-2H- pyrazol-3-yl)-5-(5-methyl- pyridin-2-yl)-benzamide 333 55

3-(5-Chloro-pyridin-2-yl)-N-(5- methyl-pyrazin-2-ylmethyl)-5- (2-propyl-2H-pyrazol-3-yl)- benzamide 447 56

3-(5-Chloro-pyridin-2-yl)-5-(2- propyl-2H-pyrazol-3-yl)-N-(1- pyrazin-2-yl-ethyl)-benzamide 447 57

3-(5-Chloro-pyridin-2-yl)-N- ((S)-2-hydroxy-1-methyl-ethyl)- 5-(2-propyl-2H-pyrazol-3-yl)- benzamide 399 58

3-(5-Chloro-pyridin-2-yl)-N- cyclopropyl-5-(2-propyl-2H- pyrazol-3-yl)-benzamide 381 59

N-[(R)-2-(4-Acetyl-piperazin-1- yl)-1-methyl-ethyl]-3-(2- isopropyl-2H-pyrazol-3-yl)-5- (5-methyl-pyridin-2-yl)- benzamide 489 60

3-(5-Chloro-pyridin-2-yl)-5-(2- isobutyl-2H-pyrazol-3-yl)-N-(1- pyrazin-2-yl-ethyl)-benzamide 461 61

3-(5-Chloro-pyridin-2-yl)-5-(2- isobutyl-2H-pyrazol-3-yl)-N-(5- methyl-pyrazin-2-ylmethyl)- benzamide 461 62

N-[(R)-2-(4-Acetyl-piperazin-1- yl)-1-methyl-ethyl]-3-(5-chloro- pyridin-2-yl)-5-(2-isopropyl-2H- pyrazol-3-yl)-benzamide 509 63

3-(5-Chloro-pyridin-2-yl)-N- cyclopropyl-5-(1-isopropyl-2H- pyrazol-3-yl)-benzamide 381 64

3-(5-Chloro-pyridin-2-yl)-N- ((S)-2-hydroxy-1-methyl-ethyl)- 5-(2-isopropyl-2H-pyrazol-3- yl)-benzamide 399 65

3-(2-Cyclopropylmethyl-2H- pyrazol-3-yl)-N-(5-methyl- pyrazin-2-ylmethyl)-5-(5- methyl-pyridin-2-yl)-benzamide 439 66

3-(2-Cyclopropylmethyl-2H- pyrazol-3-yl)-5-(5-methyl- pyridin-2-yl)-N-(1-pyrazin-2-yl- ethyl)-benzamide 439 67

3-(2-Cyclopropylmethyl-2H- pyrazol-3-yl)-N-((S)-2-hydroxy- 1-methyl-ethyl)-5-(5-methyl- pyridin-2-yl)-benzamide 391 68

N-Cyclopropyl-3-(2- cyclopropylmethyl-2H-pyrazol- 3-yl)-5-(5-methyl-pyridin-2-yl)- benzamide 373 69

3-(2-Cyclobutyl-2H-pyrazol-3- yl)-N-(5-methyl-pyrazin-2- ylmethyl)-5-(5-methyl-pyridin- 2-yl)-benzamide 439 70

3-(2-Cyclobutyl-2H-pyrazol-3- yl)-N-((S)-2-hydroxy-1-methyl- ethyl)-5-(5-methyl-pyridin-2- yl)-benzamide 391 71

3-(2-Cyclobutyl-2H-pyrazol-3- yl)-N-cyclopropyl-5-(5-methyl- pyridin-2-yl)-benzamide 373 72

3-(2-Isobutyl-2H-pyrazol-3-yl)- N-(5-methyl-pyrazin-2- ylmethyl)-5-(5-methyl-pyridin- 2-yl)-benzamide 441 73

3-(2-Isobutyl-2H-pyrazol-3-yl)- 5-(5-methyl-pyridin-2-yl)-N-(1- pyrazin-2-yl-ethyl)-benzamide 441 74

N-Cyclopropyl-3-(2-isobutyl- 2H-pyrazol-3-yl)-5-(5-methyl- pyridin-2-yl)-benzamide 375 75

3-(3-Fluoro-5-methyl-pyridin-2- yl)-5-(2-isopropyl-2H-pyrazol- 3-yl)-N-(5-methyl-pyrazin-2- ylmethyl)-benzamide 445 76

3-(2-Isopropyl-2H-pyrazol-3- yl)-N-(5-methyl-pyrazin-2- ylmethyl)-5-(5-methyl-pyridin- 2-yl)-benzamide 427 77

3-(3-Chloro-5-methyl-pyridin-2- yl)-5-(2-isopropyl-2H-pyrazol- 3-yl)-N-(5-methyl-pyrazin-2- ylmethyl)-benzamide 461 78

3-(5-Isopropyl-pyrazin-1-yl)-N- (5-methyl-pyrazin-2-ylmethyl)- 5-(5-methyl-pyridin-2-yl)- benzamide 427 79

N-(5-Methyl-pyrazin-2- ylmethyl)-3-(5-methyl-pyridin- 2-yl)-5-(5-trifluoromethyl- pyrazol-1-yl)-benzamide 453 80

N-(5-Methyl-pyrazin-2- ylmethyl)-3-(5-methyl-pyridin- 2-yl)-5-(3-trifluoromethyl- pyrazol-1-yl)-benzamide 453 81

3-(5-Methyl-pyridin-2-yl)-N-(1- pyrazin-2-yl-ethyl)-5-(5- trifluoromethyl-pyrazol-1-yl)- benzamide 453 82

N-Cyclopropyl-3-(5-methyl- pyridin-2-yl)-5-(5- trifluoromethyl-pyrazol-1-yl)- benzamide 83

3-(5-Isobutyl-pyrazol-1-yl)-N- (5-methyl-pyrazin-2-ylmethyl)- 5-(5-methyl-pyridin-2-yl)- benzamide 441 84

3-(5-Isobutyl-pyrazol-1-yl)-5- (5-methyl-pyridin-2-yl)-N-(1- pyrazin-2-yl-ethyl)-benzamide 441 85

N-((S)-2-Hydroxy-1-methyl- ethyl)-3-(5-isobutyl-pyrazol-1- yl)-5-(5-methyl-pyridin-2-yl)- benzamide 393 86

N-Cyclopropyl-3-(5-isobutyl- pyrazol-1-yl)-5-(5-methyl- pyridin-2-yl)-benzamide 375 87

3-(5-Methyl-pyridin-2-yl)-5-(3- pentafluoroethyl-pyrazol-1-yl)- N-(1-pyrazin-2-yl-ethyl)- benzamide 503 88

N-(5-Methyl-pyrazin-2- ylmethyl)-3-(5-methyl-pyridin- 2-yl)-5-(3-pentaflurooethyl- pyrazol-1-yl)-benzamide 503 89

N-Cyclopropyl-3-(5-methyl- pyridin-2-yl)-5-(3- pentafluoroethyl-pyrazol-1-yl)- benzamide 437 90

3-(5-Chloro-pyridin-2-yl)-N- ((S)-2-hydroxy-1-methyl-ethyl)- 5-(2-isobutyl-2H-pyrazol-3-yl)- benzamide 91

3-(5-Chloro-pyridin-2-yl)-N- cyclopropyl-5-(2-isobutyl-2H- pyrazol-3-yl)-benzamide 92

3-(2-tert-Butyl-2H-pyraozl-3- yl)-N-(5-methyl-pyrazin-2- ylmethyl)-5-(5-methyl-pyridin- 2-yl)-benzamide 93

3-(2-tert-Butyl-2H-pyrazol-3- yl)-N-((S)-2-hydroxy-1-methyl- ethyl)-5-(5-methyl-pyridin-2- yl)-benzamide 94

3-(2-Isopropyl-2H-pyrazol-3- yl)-N-(6-methyl-pyridazin-3- ylmethyl)-5-(5-methyl-pyridin- 2-yl)-benzamide 95

3-(2-Isobutyl-2H-pyrazol-3-yl)- N-(6-methyl-pyridazin-3- ylmethyl)-5-(5-methyl-pyridin- 2-yl)-benzamide 96

3-[2-(3-Methyl-oxetan-3- ylmethyl)-2H-pyrazol-3-yl]-N- (5-methyl-pyrazin-2-ylmethyl)- 5-(5-methyl-pyridin-2-yl)- benzamide 97

N-((S)-2-Hydroxy-1-methyl- ethyl)-3-[2-(3-methyl-oxetan-3- ylmethyl)-2H-pyrazol-3-yl]-5- (5-methyl-pyridin-2-yl)- benzamide 98

3-(5-Chloro-pyridin-2-yl)-N-(6- methyl-pyridazin-3-ylmethyl)-5- (2-propyl-2H-pyrazol-3-yl)- benzamide 99

3-(2-Cyclopropylmethyl-2H- pyrazol-3-yl)-N-(6-methyl- pyridazin-3-ylmethyl)-5-(5- methyl-pyridin-2-yl)-benzamide 100

3-(2-Isopropoxy-2H-pyrazol-3- yl)-N-(5-methyl-pyrazin-2- ylmethyl)-5-(5-methyl-pyridin- 2-yl)-benzamide 101

3-(5-Isobutyl-pyrazol-1-yl)-N- (6-methyl-pyridazin-3- ylmethyl)-5-(5-methyl-pyridin- 2-yl)-benzamide 441 Synthesis

Compounds of the present invention can be made by a variety of methods depicted in the illustrative synthetic reaction schemes shown and described below.

The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention can be synthesized, and various modifications to these synthetic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application.

The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about −78° C. to about 150° C., more preferably from about 0° C. to about 125° C., and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20° C.

Scheme A below illustrates one synthetic procedure usable to prepare specific compounds of formula I, wherein Y is an optional leaving group, R is lower alkyl, and X, R³, R⁴, R⁵, R⁶, R¹¹, R¹², R^(a) and R^(b) are as defined herein.

In step 1 of Scheme A, nitrobenzoic acid a is subject to iodination under sulfuric acid conditions to afford iodo-nitrobenzoic acid b. In step 2 benzoic acid compound b is reacted with arylboronic acid compound c in the presence of tetrakis-(triphenylphosphine)palladium catalyst to afford nitro-biphenyl acid compound d. The acid group of nitro-biphenyl acid d is protected by esterification in step 3 to form nitro-biphenyl acid ester e. Nitro-biphenyl ester e is then subject to reduction to form biphenylamine f in step 4. An iodination reaction is carried out in step 5 by treating biphenylamine f with methylene iodide or like iodination reagent to afford iodo compound g. In step 6 the ester group of compound g is hydrolyzed to give acid compound h. In step 7 an amide formation is achieved by reaction of biphenyl iodo compound h with amine i in the presence of carbodiimide, to afford compound j.

In step 8, compound j is reacted with pyrazole k in the presence of copper iodide to afford pyrazol-1-yl substituted compound m, which is a compound of formula I in accordance with the invention.

Alternatively, instead of step 8, step 9 may be carried out wherein compound j is treated with pyrazol-3-boronic acid compound n in the presence of a palladium catalyst such as tetrakis-(triphenylphosphine)palladium to afford pyrazol-3-yl substituted compound o, which is a compound of formula I in accordance with the invention.

In yet another alternative compound j may be reacted with pyrazol-4-boronic acid compound p in the presence of a palladium catalyst such as tetrakis-(triphenylphosphine)palladium in step 10 to afford pyrazol-4-yl substituted compound q, which is a compound of formula I in accordance with the invention.

Many variations of Scheme A are possible and will suggest themselves to those skilled in the art. For example, n many embodiments steps 8-10 may be carried out prior to steps 6 and 7. The resulting pyrazol-substituted compound (not shown) would then undergoes ester hydrolyisis as in step 6, followed by amide formation as in step 7, to provide compounds m, o or q.

Scheme B below relates another synthetic route to compounds of the invention, wherein Y is an optional leaving group, R is lower alkyl, and X, R³, R⁴, R⁵, R⁶, R¹¹, R¹², R^(a) and R^(b) are as defined herein.

In step 1 of Scheme B, iodo-bromo-benzoic acid ester r is reacted with bis(pinacolato)-diborane in the presence of a palladium catalyzt to yield pinacoloato-borane benzoic acid ester compound s. Compound s then undergoes a Buchwald coupling in step 2 by reaction with aryl bromide t to afford aryl benzoic acid ester compound u. Compound u may then in step 3, be reacted with pyrazole k in the presence of copper iodide to afford pyrazol-1-yl substituted ester compound v. Alternatively, step 4 may be carried out by reacting compound p with pyrazol-3-boronic acid compound n in the presence of a palladium catalyst such as tetrakis-(triphenylphosphine)palladium to afford pyrazol-3-yl substituted compound w. As yet another alternative, compound u may be reacted with pyrazol-4-boronic acid compound p in the presence of a palladium catalyst such as tetrakis-(triphenylphosphine)palladium in step 5 to afford pyrazol-4-yl substituted compound x. Compounds v, w and x then undergo ester hydrolysis and reaction with amine i, as shown in steps 6 and 7 of Scheme A, to afford pyrazole-substituted compounds m, o and q, which are compounds of formula I in accordance with the invention.

Specific details for producing compounds of the invention are described in the Examples section below.

Utility

The compounds of the invention are usable for the treatment of a wide range of genitorurinary diseases, conditions and disorders, including urinary tract disease states associated with bladder outlet obstruction and urinary incontinence conditions such as reduced bladder capacity, frequency of micturition, urge incontinence, stress incontinence, bladder hyperreactivity, benign prostatic hypertrophy (BPH), prostatitis, detrusor hyperreflexia, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urethritis, prostatitits, pelvic pain syndrome, prostatodynia, cystitis, and idiophatic bladder hypersensitivity, and other symptoms related to overactive bladder.

The compounds of the invention are expected to find utility as analgesics in the treatment of diseases and conditions associated with pain from a wide variety of causes, including, but not limited to, inflammatory pain such as pain associated with arthritis (including rheumatoid arthritis pain and osteoarthritis pain), surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine or cluster headaches, nerve injury, neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, cancer pain, viral, parasitic or bacterial infection, post-traumatic injuries (including fractures and sports injuries), and pain associated with functional bowel disorders such as irritable bowel syndrome.

Further, compounds of the invention are useful for treating respiratory disorders, including chronic obstructive pulmonary disorder (COPD), asthma, bronchospasm, and the like.

Additionally, compounds of the invention are useful for treating gastrointestinal disorders, including Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, pain associated with GI distension, and the like.

Administration and Pharmaceutical Composition

The invention includes pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients.

In general, the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, preferably 1-100 mg daily, and most preferably 1-30 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this Application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease.

Compounds of the invention may be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The preferred manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.

A compound or compounds of the invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.

The compounds of the invention may be formulated in a wide variety of oral administration dosage forms. The pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salts thereof as the active component. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about one (1) to about seventy (70) percent of the active compound. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be as solid forms suitable for oral administration.

Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

The compounds of the invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatine and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

The compounds of the invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.

The compounds of the invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

The subject compounds may be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray. The formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.

The compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin The dose of drug may be controlled by a metered valve. Alternatively the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatine or blister packs from which the powder may be administered by means of an inhaler.

When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial. Compounds in transdermal delivery systems are frequently attached to an skin-adhesive solid support. The compound of interest can also be combined with a penetration enhancer, e.g., Azone (1-dodecylazacycloheptan-2-one). Sustained release delivery systems are inserted subcutaneously into the subdermal layer by surgery or injection. The subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polylactic acid.

The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

Other suitable pharmaceutical carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pa. Representative pharmaceutical formulations containing a compound of the present invention are described below.

EXAMPLES

The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.

Unless otherwise stated, all temperatures including melting points (i.e., MP) are in degrees celsius (° C.). It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product. The following abbreviations may be used in the Preparations and Examples.

Abbreviations

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DCM dichloromethane/methylene chloride

DIPEA diisopropyl ethylamine

DME 1,2-dimethoxyethane (glyme)

DMF N,N-dimethylformamide

DMAP 4-dimethylaminopyridine

dppf 1,1′-Bis(diphenylphosphino)ferrocene

ECDI 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide

EtOAc ethyl acetate

EtOH ethanol

gc gas chromatography

HMPA hexamethylphosphoramide

HOBt N-Hydroxybenzotriazole

hplc high performance liquid chromatography

mCPBA m-chloroperbenzoic acid

MeCN acetonitrile

NMM N-methyl morpoline

NMP N-methyl pyrrolidinone

TEA triethylamine

THF tetrahydrofuran

LDA lithium diisopropylamine

TLC thin layer chromatography

Preparation 1 (S)-2-Methoxy-1-methyl-ethylamine

The synthetic procedure used in this preparation is outlined below in Scheme C.

Step 1 (S)-Boc-2-amino-propanol

D-Alanine (3.5 g, 39.3 mmol) was added in small portions to a suspension of LiAlH₄ (2.89 g, 76.26 mmol) in refluxing THF. Refluxing continued for 12 hours, then the reaction mixture was cooled to 0° C., and excess reagent was quenched by careful addition of an aqueous 15% NaOH solution (3 ml) and water (9 ml). After stirring at room temperature for 10 minutes, a solution of (Boc)₂O (8.31 g, 38.13 mmol) in CH₂Cl₂ (40 ml) was added. The reaction mixture was stirred at 60° C. for 6 hours, cooled to room temperature, filtered through a pad of anhydrous Na₂SO₄, and the filtrate concentrated under vacuum. Purification of the residue by silica-gel column chromatography afforded (S)-Boc-2-amino-propanol as a white solid, yield: 63%. MS (M+H)=176.

Step 2 (S)-Boc-2-methoxy-1-methyl-ethylamine

To a solution of (S)-Boc-2-amino-propanol (2.00 g, 11.4 mmol) was successively added Ag₂O (5.89 g, 25.4 mmol) and Methyl iodide (16.00 g, 112.7 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 days. Solid was filtered off and the filtrate was concentrated under vacuum to afford (S)-Boc-2-methoxy-1-methyl-ethylamine as a colorless oil that was used without further purification.

Step 3 (S)-2-methoxy-1-methyl-ethylamine

(S)-Boc-2-methoxy-1-methyl-ethylamine was dissolved in MeOH (40 mL) and 3 M HCl (10 mL) was added. The reaction mixture was stirred overnight at room temperature, then solvent was removed under reduced pressure and the residue was co-evaporated with additional EtOH (20 mL) to afford (S)-2-methoxy-1-methyl-ethylamine as light-brown oil in hydrochloride form (1.42 g, 100%). MS (M+H)=90.

Similarly prepared was (S)-2-ethoxy-1-methyl-ethylamine.

Similarly prepared from L-alanine were (R)-2-methoxy-1-methyl-ethylamine and (R)-2-ethoxy-1-methyl-ethylamine.

Preparation 2 (S)-1-Methyl-2-morpholin-4-yl-ethylamine

The synthetic procedure used in this preparation is outlined below in Scheme D.

Step 1 Methanesulfonic acid 2-tert-butoxycarbonylamino-propyl ester

To a solution of (S)-Boc-2-amino-propanol (4.91 g, 0.028 mol), Et₃N (1.5 equiv.) in CH₂Cl₂ at 0° C. was added methanesulfonyl chloride (1.1-1.2 equiv). The reaction was stirred at 0° C. for 30 minutes. Water (5 ml) was added and the organic layer was separated, washed with saturated aqueous NaHCO₃, brine, and dried with MgSO₄. Solvent was removed under vacuum to afford methanesulfonic acid 2-tert-butoxycarbonylamino-propyl ester as a white solid, yield: 98%. MS (M+H)=254.

Step 2 (1-Methyl-2-morpholin-4-yl-ethyl)-carbamic acid tert-butyl ester

To a solution of methanesulfonic acid 2-tert-butoxycarbonylamino-propyl ester (23 mmol) in CH₃CN (20 mL) was added morpholine (28 mmol) and K₂CO₃ (23 mmol) at room temperature. The reaction mixture was brought to 50° C. and kept at the same temperature overnight. The reaction mixture was cooled and solvent was removed under reduced pressure, and the residue was treated with CH₂Cl₂ (50 mL) and H₂O (50 mL). The organic layer was separated and the aqueous layer was extracted with CH₂Cl₂. The combined organic layer was dried over Na₂SO₄. Solvent was removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate) to afford (1-methyl-2-morpholin-4-yl-ethyl)-carbamic acid tert-butyl ester as viscous liquid, yield: 62%. MS (M+H)=245.

Step 3 (S)-1-Methyl-2-morpholin-4-yl-ethylamine

To a solution of (1-methyl-2-morpholin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.30 g, 1.22 mmol) in methanol (10 mL) was added 2N HCl (5 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The solvent was removed under vacuum to give (S)-1-Methyl-2-morpholin-4-yl-ethylamine as a light yellow solid (250 mg, 96%). MS (M+H)=145.

Similarly prepared were (S)-1-Methyl-2-thiomorpholin-4-yl-ethylamine, (S)-1-[4-(2-Amino-propyl)-piperazin-1-yl]-ethanone, (S)-1-(2-Amino-propyl)-piperidin-4-ol, (S)-1-(2-Amino-propyl)-piperidin-3-ol, (S)-1-Methyl-2-(4-methyl-piperazin-1-yl)-ethylamine, (S)-1-Methyl-2-(4-methanesulfonyl-piperazin-1-yl)-ethylamine, (S)-4-(2-Amino-propyl)-piperazin-2-one, 1-Methyl-2-piperidin-1-yl-ethylamine, 1-(2-Amino-propyl)-pyrrolidin-3-ol, (S)-2-(4-Methoxy-piperidin-1-yl)-1-methyl-ethylamine, (S)-2-(3-Methoxy-piperidin-1-yl)-1-methyl-ethylamine, (S)-2-(4-Methanesulfonyl-piperidin-1-yl)-1-methyl-ethylamine, and other 2-amino-1-heterocyclyl propanes.

Preparation 3 (S)-2-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-yl)-1-methyl-ethylamine

The synthetic procedure used in this preparation is outlined below in Scheme E.

Step 1 (1-Methyl-2-oxo-2-thiomorpholin-4-yl-ethyl)-carbamic acid tert-butyl ester

To a solution of 2-tert-Butoxycarbonylamino-propionic acid (3.5 g, 18.5 mmol), HOBt (22.2 mmol), NMP (22.2 mmol) and EDCI (22.2 mmol) in CH₂Cl₂ was added thiomorpholine (2.29 g, 22.2 mmol) at 0° C. The reaction mixture was stirred at 0° C. overnight, then washed with 2% aqueous NaOH, water, brine, and dried over Na₂SO₄. The solvent was removed under vacuum to give (1-Methyl-2-oxo-2-thiomorpholin-4-yl-ethyl)-carbamic acid tert-butyl ester (5.0 g) yield 98%. MS (M+H)=275.

Step 2 [2-(1,1-Dioxo-llambda*6*-thiomorpholin-4-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester

To a solution of (1-methyl-2-oxo-2-thiomorphin-4-yl-ethyl)-carbamic acid ter-butyl ester (5.0 g, 18.2 mmol) in CH₂Cl₂ was added m-CPBA (11.4 g, 46.25 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight. Solids were removed by filtration and the filtrate was washed by Na₂S₂O₃ and dried over Na₂SO₄. Solvent was removed under vacuum to give [2-(1,1-Dioxo-llambda*6*-thiomorpholin-4-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (5.6 g), yield 100%. MS (M+H)=307.

Step 3 2-Amino-1-(1,1-dioxo-llambda*6*-thiomorpholin-4-yl)-propan-1-one

To a solution of [2-(1,1-Dioxo-llambda*6*-thiomorpholin-4-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (5.6 g, 18.2 mmol) in CH2Cl2 (70 mL) was added trifluoroacetic acid (5 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 3 hours. After removal of CH₂Cl₂ and excess trifluoroacetic acid under reduced pressure, 2-Amino-1-(1,1-dioxo-llambda*6*-thiomorpholin-4-yl)-propan-1-one (6.0 g, yield 100%) was obtained as a white solid. MS (M+H)=207.

Step 4 (S)-2-(1,1-Dioxo-llambda*6*-thiomorpholin-4-yl)-1-methyl-ethylamine

A mixture of 2-Amino-1-(1,1-dioxo-llambda*6*-thiomorpholin-4-yl)-propan-1-one (6.0 g, 18.2 mmol) and BH₃ (1 M in THF, 110 mL) was heated to reflux for 48 h, then cooled to room temperature and quenched by MeOH. The volatile was was removed under vacuum. 2 N HCl (100 mL) was added to the residue and heated to reflux for 18 h. Solvent was removed under vacuum to give (S)-2-(1,1-Dioxo-llambda*6*-thiomorpholin-4-yl)-1-methyl-ethylamine (4.5 g) as white solid, yield 90%. MS (M+H)=193.

Preparation 4 1-Pyrazin-2-yl-ethylamine

The synthetic procedure used in this preparation is outlined below in Scheme F.

To a solution of 1-pyrazin-2-yl-ethanone (2.0 g, 15.85 mmol) and ammonium acetate (19.337 g, 158.5 mmol) in methanol (50 mL) was added sodium cyanoborohydride (0.7 g, 11.1 mmol) in one portion. The reaction mixture was stirred overnight at room temperature. After removal of methanol, water (20 mL) was added to the residue and the resulting solution was basified by addition of sodium hydroxide to pH=13. The aqueous solution was extracted with dicholromethane and the combined organic phase was dried over sodium sulfate. Removal of the solvent under reduced pressure afforded 14.62 g of 1-pyrazin-2-yl-ethylamine, yield: 75%. MS (M+H)=124.

Similarly prepared from the appropriate heteroaryl methyl ketones or phenyl methyl ketones were: 1-pyridin-2-yl-ethylamine, 1-pyridin-3-yl-ethylamine, 1-pyridin-4-yl-ethylamine, 1-(2-fluoro-phenyl)-ethylamine, 1-(3-Fluoro-phenyl)-ethylamine, 1-(4-methanesulfonyl-phenyl)-ethylamine, 1-thien-3-yl-ethylamine, 1-furan-2-yl-ethylamine, 1-(5-methyl-furan)-2-yl-ethylamine, 1-thiazol-2-yl-ethylamine, 1-thien-2-yl-ethylamine, 1-pyrimidin-2-yl-ethylamine, C-(6-methyl-pyridazin-3-yl)-methylamine, C-(5-methyl-pyrazin-2-yl)-methylamine and 1-pyridazin-4-yl-ethylamine.

Preparation 5 2-Dimethylaminomethylene-4-methyl-3-oxo-pentanoic acid ethyl ester

The synthetic procedure used in this preparation is outlined below in Scheme G.

A mixture of ethyl isobutyrylacetate (15 mmol, 0.42 mL) and N,N-dimethylformamide dimethyl acetal (37.5 mmol, 5 mL) was heated to reflux for 16 hours, then cooled. The volatiles were removed in vacuo to give 1.60 g of 2-dimethylaminomethylene-4-methyl-3-oxo-pentanoic acid ethyl ester.

Preparation 6 5-Iodo-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide

The synthetic procedure used in this preparation is outlined below in Scheme H.

Step 1 3-Iodo-5-nitro-benzoic acid

To a stirred solution of iodine (137.95 g, 0.5436 mmol) in fuming sulfuric acid (250 ml) was added m-nitrobenzoic acid (64.6 g, 0.3866 mmol) at room temperature. The reaction mixture was slowly heated to 85° C. overs 2 hours and stirred at the same temperature for another 12 hours. The reaction mixture was cooled to room temperature and poured into ice, and the aqueous solution was extracted with dichloromethane. The organic phase was separated and washed with water, 2.0 M solution of Na₂S₂O₃ and brine, and then dried over Na₂SO₄. Solvent was removed under reduced pressure to yield 3-iodo-5-nitrobenzoic acid as slight yellow solid 111 g, yield 98%. MS (M+H)=294.

Step 2 4′-Methyl-5-nitro-biphenyl-3-carboxylic acid

To a stirred solution of 3-iodo-5-nitrobenzoic acid (15.48 g, 52.83 mmol) and Pd(Ph₃P)₄ (1.84 g, 1.69 mmol) in 300 ml of toluene and 50 ml of ethanol was added p-tolylboronic acid (7.87 g, 58.11 mmol) and a solution of Cs₂CO₃ (18.89 g, 58.11 mmol) in 20 ml water at room temperature. The reaction was brought to reflux for 18 hours and then cooled to room temperature. To the solution was added 2N NaOH, and the reaction mixture was stirred for 30 minutes. The organic phase was separated, and the aqueous phase was adjusted to PH<4 using 12N HCl. The resulting solid preciptate was filtered and washed with toluene to afford 13.2 g of 4′-methyl-5-nitro-biphenyl-3-carboxylic acid as light yellow solid (97.2%). MS (M+H)=258.

Step 3 4′-Methyl-5-nitro-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide

EDCI (16.17 g, 84.38 mmol) was added portion wise to a stirred solution of 4′-methyl-5-nitro-biphenyl-3-carboxylic acid (15.49 g, 60.27 mmol), HOBt (11.44 g, 84.38 mmol) and 2-amino-1-methoxy-1-propane (7 ml, 66.31 mmol) in NMP (9.29 ml, 84.38 mmol), CH₂Cl₂ (180 ml) and DMF (20 ml) at 0° C. The mixture was allowed to warm to room temperature and was stirred at the same temperature for 14 hours. The reaction mixture was washed with 2N HCl, 2N NaOH, saturated aqueous NaHCO₃, brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give 4′-methyl-5-nitro-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide as a yellow oil (16.5 g, 83.5%). MS (M+H)=329.

Step 4 5-Amino-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide

To a stirred solution of 4′-methyl-5-nitro-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (39 mmol) in 250 ml methanol was added SnCl₂ (117 mmol) in one portion at room temperature. The reaction mixture was heated to reflux for 3 hours. Solvent was removed under reduced pressure and the residue was diluted with ethyl acetate and treated with saturated NaHCO₃ solution. Solids were filtered off and the filtrate was washed with saturated aqueous NaHCO₃, brine, dried over anhydrous Na₂SO₄, filtered and concentrated in vaccuo to give 5-amino-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide as a yellow oil (10.5 g, 90.3%). MS (M+H)=299.

Step 5 5-Iodo-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide

A mixture of 5-amino-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (5.3 g, 17. 8 mmol), iso-amyl nitrite (13.5 ml, 88.9 mmol) and diiodomethane (8 ml, 106.7 mmol) was stirred at room temperature for 1 hour. The mixture was then heated to 65° C. and kept for 8 hours, LC/MS indicated that reaction completed. The reaction mixture was cooled to room temperature and the separation of iodobenzene from excess diiodomethane was effected by addition of the reaction mixture at room temperature to a stirred solution of piperidin—CH₃CN (V/V=90 ml/90 ml). A vigorous exothermic reaction ensued. The excess volatile reagents were removed by rotary evaporation at 80° C. The residue was diluted with ethyl acetate, washed with 10% hydrochloric acid, water and brine. The organic layer was separated and dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/hexanes=10:1) to yield 5-iodo-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide as a yellow solid (5.2 g, 83.8%). MS (M+H)=410.

Similarly prepared, using the appropriate amine compound in step 3, were:

5-Iodo-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide, MS (M+H)=444;

5-Iodo-4′-methyl-biphenyl-3-carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide, MS (M+H)=396;

5-Iodo-4′-methyl-biphenyl-3-carboxylic acid (1-methyl-2-morpholin-4-yl-ethyl)-amide, MS (M+H)=465;

5-Iodo-4′-methyl-biphenyl-3-carboxylic acid [2-(1,1-dioxo-llambda*6*-thiomorpholin-4-yl)-1-methyl-ethyl]-amide, MS (M+H)=513; and

5-Iodo-4′-methyl-biphenyl-3-carboxylic acid (pyrazin-2-ylmethyl)-amide, MS (M+H)=430.

Preparation 7 5-Iodo-4′-methyl-biphenyl-3-carboxylic acid

The synthetic procedure used in this preparation is outlined below in Scheme I.

Step 1 4′-Methyl-5-nitro-biphenyl-3-carboxylic acid methyl ester

To a solution of 4′-methyl-5-nitro-biphenyl-3-carboxylic acid (10.00 g, 0.039 mol) in methanol was added SOCl₂(5.09 g, 0.043 mol) at 0° C. The reaction mixture was allowed to warm to room temperature and was then heated to reflux for 2 hours. The solvent was removed in vacuo to afford 4′-Methyl-5-nitro-biphenyl-3-carboxylic acid methyl ester (9.72 g, 92%) as light yellow solid. MS (M+H)=273.

Step 2 5-Amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester

4′-Methyl-5-nitro-biphenyl-3-carboxylic acid methyl ester was reduced using SnCl₂ using the procedure of step 4 of preparation 6 to afford 5-Amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester, MS (M+H)=242.

Step 3 5-Iodo-4′-methyl-biphenyl-3-carboxylic acid methyl ester

5-Amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester was treated with methylene iodide and isoamy nitrate using the procedure of step 5 of preparation 6, to afford 5-iodo-4′-methyl-biphenyl-3-carboxylic acid, MS (M+H)=353.

Similarly prepared was 2′-fluoro-5-iodo-4′-methyl-biphenyl-3-carboxylic acid methyl ester, MS (M+H)=371.

Preparation 8 3-Iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid

The synthetic procedure used in this preparation is outlined below in Scheme J.

Step 1 3-Iodo-5-nitro-benzoic acid methyl ester

To a solution of 3-iodo-5-nitrobenzoic acid (20.00 g, 0.068 mol) in methanol (50 mL) was added SOCl₂(5.45 mL, 0.075 mol) at 0° C. The reaction mixture was allowed to warm to room temperature and was then heated to reflux for 2 hours. The reaction was cooled and solvent was removed in vacuo to afford 3-Iodo-5-nitro-benzoic acid methyl ester as light yellow solid (20.67 g, 99%). MS (M+H)=309.

Step 2 3-Nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester

A solution of 3-iodo-5-nitro-benzoic acid methyl ester (10 g, 0.0326 mol), bis(pinacolato)diboron (9.1 g, 0.0358 mol), KOAc (9.5 9 g, 0.098 mol) and PdCl₂(dppf) (798 mg, 0.98 mmol) in DMSO (40 ml) was heated to 80° C. for 4 hours under N₂ atmosphere. The mixture was cooled to room temperature and extracted with Et₂O. The combined organic phases were washed with brine and dried over Na₂SO₄. The solvent was evaporated under reduced pressure and the resulting crude 3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester was used without purification in the next step.

Step 3 3-(5-Methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester

To a solution of 2-bromo-5-methylpyridine (1.24 g, 7 mmol), Pd(PPh₃)₄ (226 mg, 0.2 mmol) and K₃PO₄(2.76 g, 13 mmol) in DME/H₂O (5 ml/1 ml) was added 3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (2.00 g, 6.5mmol) under N₂ atmosphere. The mixture was subjected to microwave radiation at 130° C. for 0.5 hours. The reaction mixture was cooled and solvent was evaporated under reduced pressure. The residue was purified by flash-chromatography (CH₂Cl₂/MeOH) to give 3-(5-methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester as a white solid (700 mg, 40%).

Step 4 3-Amino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester

To a solution of 3-(5-methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester (4 g, 14.7 mmol) in methanol/ethyl acetate was added SnCl₂ (11.15 g, 58.8 mmol) at room temperature. The reaction mixture was refluxed for 3 hours and then cooled. Solvent was removed under reduced pressure and the residue was dissolved in H₂O and basified by addition of Na₂CO₃ to pH=9. The mixture was extracted with CH₂Cl₂, and the organic phase was washed with water, brine, and dried over Na₂SO₄. The solvent was removed under reduced pressure to give 3-mmino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (3.2 g, 90%) as white solid.

Step 5 3-Iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester

5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester was treated with methylene iodide and isoamy nitrate using the procedure of step 5 of preparation 6, to afford 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester, MS (M+H)=353.

Step 6 3-Iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid

A solution of LiOH hydrate (82 mg, 1.94 mmol) in H₂O (7 mL) was added dropwise to a suspension of 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (526 mg, 1.49 mmol) in THF (4 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred until the reaction solution turned into clear. Solvent was removed under vacuum and the resulting aqueous solution was acidified by 10% HCl to pH=6˜7. The resulting precipitate was collected and dried to afford 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid (470 mg, 93%). MS (M+H)=340.

Preparation 9 3-Bromo-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester

The synthetic procedure used in this preparation is outlined below in Scheme K.

Step 1 3-Bromo-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester

3-Bromo-5-iodo-benzoic acid methyl ester (14.16 g, 41.53 mmol), bis(pinacolato)-diborane (11.60 g, 45.7 mmol), PdCl₂(dppf)₂ (1.02 g, 1.256 mmol) and potassium acetate (12.22 g, 124.6 mmol) were added to 50 mL of DMSO, and the reaction mixture was stirred at 80° C. for 20 hours, then cooled to room temperature. The reaction mixture was diluted with water and extracted with diethyl ether. The combined organic extracts were dried over Mg SO₄, filtered, and concentrated under reduced pressure to give 18.5 g of 3-bromo-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester, which was used directly in the next step without further purification.

Step 2 3-Bromo-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester

A mixture of 2-bromo-5-methyl-pyridine (10.27 g, 59.68 mmol) and palladium tetrakis(triphenylphosphine) (1.88 g, 1.65 mmol) in 300 mL DME was stirred at 60° C. under nitrogen for 30 minutes. To this mixture was added 3-bromo-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (18.5 g, 54.25 mmol), followed by K₃PO₄ 23.03 g, 108.5 mmol) in 40 mL water. The mixture was refluxed for eight hours, then cooled to room temperature and partitioned between water and EtOAc. The combined organic layers were washed with water, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (5:1 EtOAc/hexanes) to give 8.5 g of 3-bromo-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester, MS (M+H)=306.

Similarly prepared were:

-   -   3-Bromo-5-(2-chloro-5-methyl-pyridin-2-yl)-benzoic acid methyl         ester, MS (M+H)=341;     -   3-Bromo-5-(2-fluoro-5-methyl-pyridin-2-yl)-benzoic acid methyl         ester, MS (M+H)=325; and     -   3-Bromo-5-(5-chloro-pyridin-2-yl)-benzoic acid methyl ester, MS         (M+H)=327.

Preparation 10 1-Isopropyl-1H-pyrazole-5-boronic acid

The synthetic procedure used in this preparation is outlined below in Scheme L.

Step 1 1-Isopropyl-1H-pyrazole

To a suspension of NaH (14 g, 0.35 mol 60% in mineral oil) in DMF (120 mL) was added dropwise of a solution of pyrazole (20 g, 0.29 mol) in DMF (30 mL) at ° C. After addition, the suspension was stirred for 1 hour at room temperature. Isopropyl bromide (53.4 g, 0.44 mol) was added dropwise, and the reaction mixture was stirred at room temperature for 2 hours. Water was added to quench the reaction and the mixture was extracted with diethyl ether. The combined ether layers were washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was distilled under vacuum to afford 1-isopropyl-1H-pyrazole as a colorless liquid (15.0 g, 46.4%).

Step 2 1-Isopropyl-1H-pyrazole-5-boronic acid

To a solution of isopropylpyrazole (5.0 g, 45.5 mmol) in THF (100 mL) was added n-butyl lithium (31 mL, 50 mmol, 1.6 M in hexane) at −78° C. The mixture was kept stirring at the same temperature for 30 min. and was allowed to warm to 0° C. and stirred for another 30 min. Before adding tri-n-butyl borate (12.6 g, 55 mmol) as one portion, the reaction mixture was cooled to −78° C. After addition, the mixture was stirred at −78° C. for 1 h. and was allowed to warm to r.t. slowly and stirred overnight. The reaction mixture was quenched by saturated ammonium chloride. The organic phase was separated and the aqueous phase was extracted with ethyl ether (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate. Solvent was removed to afford 1-isopropyl-1H-pyrazole-5-boronic acid as a viscous oil (5.7 g).

Similarly prepared, using the appropriate alkyl bromides, were:

1-methyl-1H-pyrazole-5-boronic acid;

1-ethyl-1H-pyrazole-5-boronic acid;

1-n-propyl-1H-pyrazole-5-boronic acid;

1-isobutyl-1H-pyrazole-5-boronic acid;

1-tert-butyl-1H-pyrazole-5-boronic acid;

1-cyclobutyl-1H-pyrazole-5-boronic acid; and

1-cyclpropylmethyl-1H-pyrazole-5-boronic acid.

Example 1 4′-Methyl-5-(1-methyl-1H-pyrazol-4-yl)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide

The synthetic procedure used in this preparation is outlined below in Scheme M.

A mixture solution of 5-iodo-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (85.9 mg, 0.2100 mmol), 1-methyl-pyrazol-4-boronic acid (31.28 mg, 0.2300 mmol), Cs₂CO₃ (0.23 mL, 1 N, 0.23 mmol) and Pd(Ph₃P)₄ (17.0 mg, 0.0146 mmol) in toluene (1.5 mL) and THF (1.5 mL) was stirred under microwave heating for 30 minutes at 130° C. After reaction mixture was cooled to room temperature, the solvent was removed under vacuum and the residue was purified by preparative HPLC to afford 4′-methyl-5-(1-methyl-1H-pyrazol-4-yl)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide as white solid (42.68 mg, 56%). MS (M+H)=364.

Similarly prepared was 4′-methyl-5-(1H-pyrazol-4-yl)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide, MS (M+H)=350.

Additional compounds prepared by the above procedure are shown in Table 1.

Example 2 5-Isopropyl-1-[5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′-methyl-biphenyl-3-yl]-1H-pyrazole-3-carboxylic acid ethyl ester

The synthetic procedure used in this preparation is outlined below in Scheme N.

To 2-dimethylaminomethylene-4-methyl-3-oxo-pentanoic acid ethyl ester (1.60 g, 7.5 mmol) was added 5-hydrazino-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (7.5 mmol, 2.62 g), followed by EtOH (25 mL). The mixture was heated to 60° C. and kept at that temperature for 12 hours. The reaction mixture was cooled and EtOH was removed in vacuo. The residue was purified by flash column chromatography, eluting with n-hexanes:EtOAc=4:1 to give 2.95 g of 5-isopropyl-1-[5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′-methyl-biphenyl-3-yl]-1H-pyrazole-3-carboxylic acid ethyl ester as white solid (85%). MS (M+H)=464.

Additional compounds prepared by the above procedure are shown in Table 1.

Example 3 2′-Fluoro-5-(2-isopropyl-2H-pyrazol-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide

The synthetic procedure used in this preparation is outlined below in Scheme O.

Step 1 2′-Fluoro-5-(2-isopropyl-2H-pyrazol-3-yl)-4′-methyl-biphenyl-3-carboxylic acid methyl ester

To a microwave vessel was added 2′-fluoro-5-iodo-4′-methyl-biphenyl-3-carboxylic acid methyl ester (1.91 g, 5.4 mmol), 2-isopropyl-2H-pyrazole-3-boronic acid (1.08 g, 7.02 mmol), KOAc (1.59 g, 16.2 mmol), Pd(PPh₃)₄ (0.187 g, 0.16 mmol), dimethylglycol (15 mL) and water (3 mL). The mixture was flushed with N₂ before submitting to microwave heating at 130° C. for 1 hour. After cooling down to room temperature, the reaction mixture was extracted with EtOAc and the combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column to afford 2′-fluoro-5-(2-isopropyl-2H-pyrazol-3-yl)-4′-methyl-biphenyl-3-carboxylic acid methyl ester as a viscous oil (1.0 g, 55.2%).

Step 2 2′-Fluoro-5-(2-isopropyl-2H-pyrazol-3-yl)-4′-methyl-biphenyl-3-carboxylic acid

A solution of LiOH hydrate (82 mg, 1.94 mmol) in H₂O (7 mL) was added dropwise to a solution of 2′-fluoro-5-(2-isopropyl-2H-pyrazol-3-yl)-4′-methyl-biphenyl-3-carboxylic acid methyl ester (524 mg, 1.49 mmol) in THF (4 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred until the reaction solution turned into clear. Solvent was removed under vacuum and the resulting aqueous solution was acidified by 10% HCl to pH=6-7. The resulting precipitate was collected and dried to afford 2′-fluoro-5-(2-isopropyl-2H-pyrazol-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (468 mg, 93%).

Step 3 2′-Fluoro-5-(2-isopropyl-2H-pyrazol-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide

EDCI (54.0 mg, 0.282 mmol) was added in one portion to a solution of 2′-fluoro-5-(2-isopropyl-2H-pyrazol-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (77.4 mg, 0.229 mmol), HOBt (40.0 mg, 0.296 mmol) and NMP (101.5 mg, 1.000 mmol) in CH₂Cl₂(5 mL) at 0° C. After the reaction stirred at the same temperature for 1 hour, 2-amino-propan-1-ol (54 mg, 0.72 mmol) was added. The mixture was allowed to warm to room temperature and was stirred overnight. Solvent was removed under reduced pressure and the residue was purified by column chromatography to afford 2′-Fluoro-5-(2-isopropyl-2H-pyrazol-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide as white solid (54 mg, 46%). MS (M+H)=396.

Similarly prepared, starting with 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester instead of 2′-fluoro-5-iodo-4′-methyl-biphenyl-3-carboxylic acid methyl ester, was N-(2-Hydroxy-1-methyl-ethyl)-3-(2-isopropyl-2H-pyrazol-3-yl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=379.

Similarly prepared, starting with 3-iodo-5-(3-chloro-5-methyl-pyridin-2-yl)-benzoic acid methyl ester instead of 2′-fluoro-5-iodo-4′-methyl-biphenyl-3-carboxylic acid methyl ester, and replacing 2-amino-propan-1-ol in step 3 with 1-pyrazin-2-yl-ethylamine, was 3-(3-chloro-5-methyl-pyridin-2-yl)-5-(2-isopropyl-2H-pyrazol-3-yl)-N-(1-pyrazin-2-yl-ethyl)-benzamide, MS (M+H)=461.

Additional compounds made using the above procedure are shown in Table 1.

Example 4 3-(2-Cyclopropylmethyl-2H-pyrazol-3-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide

The synthetic procedure used in this preparation is outlined below in Scheme P.

Step 1 3-(2-Cyclopropylmethyl-2H-pyrazol-3-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester

3-Bromo-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (1.0 g, 3.27 mmol) and palladium tetrakis(triphenylphosphine) (0.189 g, 0.164 mmol) were added to 25 mL DME, and the mixture was stirred at 60° C. for 10 minutes. 1-Cyclopropylmethyl-1H-pyrazole-5-boronic acid (0.65 g, 3.92 mmol) was added, followed by a solution of K₃PO₄ (1.39 g, 6.54 mmol) in 5 mL water. The mixture was refluxed for six hours, then cooled to room temperature and partitioned between water and EtOAc. The combined organic layers were washed with water, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (3:1 EtOAc/hexanes) to give 1.14 g of 3-(2-cyclopropylmethyl-2H-pyrazol-3-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester, MS (M+H)=348.

Step 2 3-(2-Cyclopropylmethyl-2H-pyrazol-3-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid

3-(2-Cyclopropylmethyl-2H-pyrazol-3-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (1.14 g, 3.27 mmol was dissolved in 20 mL MeOH, and 3N aqueous NaOH (3 mL) was added. The reaction mixture was stirred at room temperature for three hours, then concentrated under reduced pressure. The residue was acidified to pH 3 and extracted with EtOAc. The combined organic layers were dried over MgSO₄, filtered and concentrated under reduced pressure to give 0.9 g of 3-(2-cyclopropylmethyl-2H-pyrazol-3-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid, MS (M+H)=334.

Step 3 3-(2-Cyclopropylmethyl-2H-pyrazol-3-yl) -N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide

3-(2-Cyclopropylmethyl-2H-pyrazol-3-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid (0.120 g, 0.36 mmol), C-(5-methyl-pyrazin-2-yl)-methylamine (0.044 g, 0.36 mmol), EDCI (0.103 g, 0.54 mmol), HOBt (0.073 g, 0.54 mmol), and NMM (0.183 g, 1.80 mmol) were added to 7 mL of dichloromethane The reaction mixture was stirred for 48 hours at room temperature, then concentrated under reduced pressure. The residue was purified via flash chromatography (5:1 EtOAc/hexanes) to give 0.14 g of 3-(2-cyclopropylmethyl-2H-pyrazol-3-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=439.

Similarly prepared, using the appropriate amines in step 3, were:

3-(2-Cyclopropylmethyl-2H-pyrazol-3-yl)-5-(5-methyl-pyridin-2-yl)-N-(1-pyrazin-2-yl-ethyl)-benzamide, MS (M+H)=439;

3-(2-Cyclopropylmethyl-2H-pyrazol-3-yl)-N-((S)-2-hydroxy-1-methyl-ethyl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=391; and

N-Cyclopropyl-3-(2-cyclopropylmethyl-2H-pyrazol-3-yl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=373.

Similarly prepared, using the appropriate N-substituted pyrazole boronic acid in step 1, were:

N-(5-Methyl-pyrazin-2-ylmethyl)-3-(5-methyl-pyridin-2-yl)-5-(2-propyl-2H-pyrazol-3-yl)-benzamide, MS (M+H)=427;

N-(5-Methyl-pyrazin-2-ylmethyl)-3-(2-methyl-2H-pyrazol-3-yl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=399;

3-(2-Isopropyl-2H-pyrazol-3-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=427

3-(2-Isobutyl-2H-pyrazol-3-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=441;

3-(2-Cyclobutyl-2H-pyrazol-3-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=439; and

3-(2-tert-Butyl-2H-pyrazol-3-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=441.

Additional compounds made using the above procedure are shown in Table 1.

Example 5 4′-Methyl-5-pyrazol-1-yl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide

The synthetic procedure used in this preparation is outlined below in Scheme Q.

To a stirred solution of 5-iodo-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (0.15 g, 0.367 mmol) in 1 ml DMF was added pyrazole (0.062 g, 0.917 mmol), CuI (0.03667 mmol), 1,10-phenanthroline (0.0734 mmol) and Cs₂CO₃ (0.734 mmol). The mixture was subjected to microwave irridation at 150° C. for 45 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 4′-Methyl-5-pyrazol-1-yl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide, MS (M+H)=350.

Example 6 Formulations

Pharmaceutical preparations for delivery by various routes are formulated as shown in the following Tables. “Active ingredient” or “Active compound” as used in the Tables means one or more of the Compounds of Formula I.

Composition for Oral Administration

Ingredient % wt./wt. Active ingredient 20.0% Lactose 79.5% Magnesium stearate 0.5%

The ingredients are mixed and dispensed into capsules containing about 100 mg each; one capsule would approximate a total daily dosage.

Composition for Oral Administration

Ingredient % wt./wt. Active ingredient 20.0% Magnesium stearate 0.5% Crosscarmellose sodium 2.0% Lactose 76.5% PVP (polyvinylpyrrolidine) 1.0%

The ingredients are combined and granulated using a solvent such as methanol. The formulation is then dried and formed into tablets (containing about 20 mg of active compound) with an appropriate tablet machine.

Composition for Oral Administration

Ingredient Amount Active compound 1.0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 g Granulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 ml Colorings 0.5 mg Distilled water q.s. to 100 ml

The ingredients are mixed to form a suspension for oral administration.

Parenteral Formulation

Ingredient % wt./wt. Active ingredient 0.25 g Sodium Chloride qs to make isotonic Water for injection 100 ml

The active ingredient is dissolved in a portion of the water for injection. A sufficient quantity of sodium chloride is then added with stirring to make the solution isotonic. The solution is made up to weight with the remainder of the water for injection, filtered through a 0.2 micron membrane filter and packaged under sterile conditions.

Suppository Formulation

Ingredient % wt./wt. Active ingredient 1.0% Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5%

The ingredients are melted together and mixed on a steam bath, and poured into molds containing 2.5 g total weight.

Topical Formulation

Ingredients Grams Active compound 0.2-2 Span 60 2 Tween 60 2 Mineral oil 5 Petrolatum 10 Methyl paraben 0.15 Propyl paraben 0.05 BHA (butylated hydroxy anisole) 0.01 Water q.s. 100

All of the ingredients, except water, are combined and heated to about 60° C. with stirring. A sufficient quantity of water at about 60° C. is then added with vigorous stirring to emulsify the ingredients, and water then added q.s. about 100 g.

Nasal Spray Formulations

Several aqueous suspensions containing from about 0.025-0.5 percent active compound are prepared as nasal spray formulations. The formulations optionally contain inactive ingredients such as, for example, microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, and the like. Hydrochloric acid may be added to adjust pH. The nasal spray formulations may be delivered via a nasal spray metered pump typically delivering about 50-100 microliters of formulation per actuation. A typical dosing schedule is 2-4 sprays every 4-12 hours.

Example 7 P2X₃/P2X_(2/3) FLIPR (Fluorometric Imaging Plate Reader) Assay

CHO-K1 cells were transfected with cloned rat P2X₃ or human P2X_(2/3) receptor subunits and passaged in flasks. 18-24 hours before the FLIPR experiment, cells were released from their flasks, centrifuged, and resuspended in nutrient medium at 2.5×10⁵ cells/ml. The cells were aliquoted into black-walled 96-well plates at a density of 50,000 cells/well and incubated overnight in 5% CO₂ at 37° C. On the day of the experiment, cells were washed in FLIPR buffer (calcium- and magnesium-free Hank's balanced salt solution, 10 mM HEPES, 2 mM CaCl₂, 2.5 mM probenecid; FB). Each well received 100 μl FB and 100 μl of the fluorescent dye Fluo-3 AM [2 μM final conc.]. After a 1 hour dye loading incubation at 37° C., the cells were washed 4 times with FB, and a final 75 FB was left in each well.

Test compounds (dissolved in DMSO at 10 mM and serially diluted with FB) or vehicle were added to each well (25 μl of a 4× solution) and allowed to equilibrate for 20 minutes at room temperature. The plates were then placed in the FLIPR and a baseline fluorescence measurement (excitation at 488 nm and emission at 510-570 nm) was obtained for 10 seconds before a 100 μl/well agonist or vehicle addition. The agonist was a 2× solution of α,β-meATP producing a final concentration of 1 μM (P2X₃) or 5 μM (P2X_(2/3)). Fluorescence was measured for an additional 2 minutes at 1 second intervals after agonist addition. A final addition of ionomycin (5 μM, final concentration) was made to each well of the FLIPR test plate to establish cell viability and maximum fluorescence of dye-bound cytosolic calcium. Peak fluorescence in response to the addition of α,β-meATP (in the absence and presence of test compounds) was measured and inhibition curves generated using nonlinear regression. PPADS, a standard P2X antagonist, was used as a positive control.

Using the above procedure, compounds of the invention exhibited activity for the P2X₃ receptor. The compound 3-(2-cyclobutyl-2H-pyrazol-3-yl)-N-((S)-2-hydroxy-1-methyl-ethyl)-5-(5-methyl-pyridin-2-yl)-benzamide, for example, exhibited a pIC₅₀ of approximately 8.67 for the P2X₃ receptor, and the compound 3-(5-isobutyl-pyrazol-1-yl)-N-(6-methyl-pyridazin-3-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide showed a pKi of approximately 7.67 for the P2X_(2/3) receptor, using the above assay.

Example 8 In vivo Assay for Asthma and Lung Function

BALb/cJ mice are immunized with a standard immunization protocol. Briefly, mice (N=8/group) are immunized i.p. with ovalbumin (OVA; 10 μg) in alum on days 0 and 14. Mice are then challenged with aerosolized OVA (5%) on day 21 and 22. Animals receive vehicle (p.o.) or a compound of the invention (100 mg/kg p.o.) all starting on day 20.

Lung function is evaluated on day 23 using the Buxco system to measure PenH in response to an aerosol methacholine challenge. Mice are then euthanized and plasma samples collected at the end of the study.

Example 9 Volume Induced Bladder Contraction Assay

Female Sprague-Dawley rats (200-300 g) were anesthetized with urethane (1.5 g/kg, sc). The animals were tracheotomized, and a carotid artery and femoral vein were cannulated for blood pressure measurement and drug administration, respectively. A laparotomy was performed and the ureters were ligated and transected proximal to the ligation. The external urethral meatus was ligated with silk suture and the urinary bladder was cannulated via the dome for saline infusion and bladder pressure measurement.

Following a 15-30 minute stabilization period the bladder was infused with room temperature saline at 100 μl/min until continuous volume-induced bladder contractions (VIBCs) were observed. The infusion rate was then lowered to 3-5 μl/min for 30 minutes before the bladder was drained and allowed to rest for 30 minutes. All subsequent infusions were performed as indicated except the lower infusion rate was maintained for only 15 minutes instead of 30 minutes. Bladder filling and draining cycles were repeated until the threshold volumes (TV; the volume needed to trigger the first micturition bladder contraction) varied by less than 10% for two consecutive baselines and contraction frequency was within 2 contractions for a 10 minute period following the slower infusion rate. Once reproducible TVs and VIBCs were established the bladder was drained and the animal was dosed with drug or vehicle (0.5 ml/kg, i.v.) 3 minutes prior to the start of the next scheduled infusion.

Example 10 Formalin Pain Assay

Male Sprague Dawley rats (180-220 g) are placed in individual Plexiglas cylinders and allowed to acclimate to the testing environment for 30 min. Vehicle, drug or positive control (morphine 2 mg/kg) is administered subcutaneously at 5 ml/kg. 15 min post dosing, formalin (5% in 50 μl) is injected into plantar surface of the right hind paw using a 26-gauge needle. Rats are immediately put back to the observation chamber. Mirrors placed around the chamber allow unhindered observation of the formalin-injected paw. The duration of nociphensive behavior of each animal is recorded by a blinded observer using an automated behavioral timer. Hindpaw licking and shaking/lifting are recorded separately in 5 min bin, for a total of 60 min. The sum of time spent licking or shaking in seconds from time 0 to 5 min is considered the early phase, whereas the late phase is taken as the sum of seconds spent licking or shaking from 15 to 40 min. A plasma sample is collected.

Example 11 Colon Pain Assay

Adult male Sprague-Dawley rats (350-425 g; Harlan, Indianapolis, Ind.) are housed 1-2 per cage in an animal care facility. Rats are deeply anesthetized with pentobarbital sodium (45 mg/kg) administered intraperitoneally. Electrodes are placed and secured into the external oblique musculature for electromyographic (EMG) recording. Electrode leads are tunneled subcutaneously and exteriorized at the nape of the neck for future access. After surgery, rats are housed separately and allowed to recuperate for 4-5 days prior to testing.

The descending colon and rectum are distended by pressure-controlled inflation of a 7-8 cm-long flexible latex balloon tied around a flexible tube. The balloon is lubricated, inserted into the colon via the anus, and anchored by taping the balloon catheter to the base of the tail. Colorectal distension (CRD) is achieved by opening a solenoid gate to a constant pressure air reservoir. Intracolonic pressure is controlled and continuously monitored by a pressure control device. Response is quantified as the visceromotor response (VMR), a contraction of the abdominal and hindlimb musculature. EMG activity produced by contraction of the external oblique musculature is quantified using Spike2 software (Cambridge Electronic Design). Each distension trial lasts 60 sec, and EMG activity is quantified for 20 sec before distension (baseline), during 20 sec distension, and 20 sec after distention. The increase in total number of recorded counts during distension above baseline is defined as the response. Stable baseline responses to CRD (10, 20, 40 and 80 mmHg, 20 seconds, 4 minutes apart) are obtained in conscious, unsedated rats before any treatment.

Compounds are evaluated for effects on responses to colon distension initially in a model of acute visceral nociception and a model of colon hypersensitivity produced by intracolonic treatment with zymosan (1 mL, 25 mg/mL) instilled into the colon with a gavage needle inserted to a depth of about 6 cm. Experimental groups will consist of 8 rats each.

Acute visceral nociception: For testing effects of drug on acute visceral nociception, 1 of 3 doses of drug, vehicle or positive control (morphine, 2.5 mg/kg) are administered after baseline responses are established; responses to distension are followed over the next 60-90 minutes.

Visceral hypersensitivity: For testing effects of drug or vehicle after intracolonic treatment with zymosan, intracolonic treatment is given after baseline responses are established. Prior to drug testing at 4 hours, responses to distension are assessed to establish the presence of hypersensitivity. In zymosan-treated rats, administration of 1 of 3 doses of drug, vehicle or positive control (morphine, 2.5 mg/kg) are given 4 hours after zymosan treatment and responses to distension followed over the next 60-90 minutes.

Example 12 Cold Allodynia in Rats with a Chronic Constriction Injury of the Sciatic Nerve

The effects of compounds of this invention on cold allodynia are determined using the chronic constriction injury (CCI) model of neuropathic pain in rats, where cold allodynia is measured in a cold-water bath with a metal-plate floor and water at a depth of 1.5-2.0 cm and a temperature of 3-4° C. (Gogas, K. R. et al., Analgesia, 1997, 3, 1-8).

Specifically, CCI, rats are anesthetized; the trifurcation of the sciatic nerve is located and 4 ligatures (4-0, or 5-0 chromic gut) are placed circumferentially around the sciatic nerve proximal to the trifurcation. The rats are then allowed to recover from the surgery. On days 4-7 after surgery, the rats are initially assessed for cold-induced allodynia by individually placing the animals in the cold-water bath and recording the total lifts of the injured paw during a 1-min period of time: The injured paw is lifted out of the water. Paw lifts associated with locomotion or body repositioning are not recorded. Rats that displayed 5 lifts per min or more on day 4-7 following surgery are considered to exhibit cold allodynia and are used in subsequent studies. In the acute studies, vehicle, reference compound or compounds of this invention are administered subcutaneously (s.c.) 30 min before testing. The effects of repeated administration of the compounds of this invention on cold allodynia are determined 14, 20 or 38 h following the last oral dose of the following regimen: oral (p.o.) administration of vehicle, reference or a compound of this invention at ˜12 h intervals (BID) for 7 days.

Example 13 Cancer Bone Pain in C3H/HeJ Mice

The effects of compounds of this invention on bone pain are determined between Day 7 to Day 18 following intramedullary injection of 2472 sarcoma cells into the distal femur of C3H/HeJ mice.

Specifically, NCTC 2472 tumor cells (American Type Culture Collection, ATCC), previously shown to form lytic lesions in bone after intramedullary injection, are grown and maintained according to ATCC recommendations. Approximately 10⁵ cellsare injected directly into the medullary cavity of the distal femur in anesthetized C3H/HeJ mice. Beginning on about Day 7, the mice are assessed for spontaneous nocifensive behaviors (flinching & guarding), palpation-evoked nocifensive behaviors (flinching & guarding), forced ambultory guarding and limb use. The effects of compounds of this invention are determined following a single acute (s.c.) administration on Day 7-Day 15. In addition, the effects of repeated (BID) administration of compounds of this invention from Day 7-Day 15 are determined within 1 hour of the first dose on Days 7, 9, 11, 13 and 15.

While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto. 

What is claimed is:
 1. A compound of formula I:

or pharmaceutically acceptable salts thereof, wherein: R¹ is 1H-pyrazol-1-yl (1A)

optionally independently substituted with one, two or three groups independently selected from C₁₋₆alkyl; C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; phenyl; amino; N—C₁₋₆alkyl-amino; N,N-di-C₁₋₆alkyl-amino halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; heterocyclyl, hetero-C₁₋₆alkyl; C₃₋₆-cycloalkyl; C₃₋₆cycloalkyl-C₁₋₆alkyl; aminocarbonyl; heterocyclylcarbonyl; C₁₋₆alkoxycarbonyl; or cyano; or R^(a) and R^(b) together with the atoms to which they are attached may form a phenyl, pyridinyl or pyrimidinyl group, each optionally substituted; and wherein R^(c) is hydrogen, C₁₋₆alkyl or halo-C₁₋₆alkyl; R² is optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl or optionally substituted thiophenyl; R³ is: hydrogen; C₁₋₆alkyl; hetero-C₁₋₆alkyl; or cyano; R⁴ is: hydrogen; C₁₋₆alkyl; or hetero-C₁₋₆alkyl; or R³ and R⁴ together with the atom to which they are attached may form a C₃₋₆ carbocyclic ring; R⁵ is: C₁₋₆alkyl; hetero-C₁₋₆alkyl; halo-C₁₋₆alkyl; N—C₁₋₆alkylamino; N,N-di-(C₁₋₆alkyl)-amino; C₃₋₇cycloalkyl; aryl; heteroaryl; heterocyclyl; C₃₋₇cycloalkyl-C₁₋₆alkyl; heteroaryl-C₁₋₆alkyl; heterocyclyl-C₁₋₆alkyl; aryl-C₁₋₆alkyl; aryloxy-C₁₋₆alkyl; —(CR^(a)R^(b))_(m)—C(O)—R⁸ wherein: m is 0 or 1; R^(a) and R^(b) each independently is: hydrogen; or C₁₋₆alkyl; and R⁸ is: hydrogen; C₁₋₆alkyl; hetero-C₁₋₆alkyl; C₃₋₇cycloalkyl; aryl; heteroaryl; heterocyclyl; C₃₋₇cycloalkyl-C₁₋₆alkyl; aryl-C₁₋₆alkyl; heteroaryl-C₁₋₆alkyl; heterocyclyl-C₁₋₆alkyl; C₃₋₇cycloalkyloxy; aryloxy; heteroaryloxy; heterocyclyloxy; C₃₋₇cycloalkyloxy-C₁₋₆alkyl; aryloxy-C₁₋₆alkyl; heteroaryloxy-C₁₋₆alkyl; heterocyclyloxy-C₁₋₆alkyl; or —NR⁹R¹⁰, wherein:  R⁹ is:  hydrogen; or  C₁₋₆alkyl; and  R¹⁰ is:  hydrogen;  C₁₋₆alkyl;  hetero-C₁₋₆alkyl;  C₃₋₇cycloalkyl;  aryl;  heteroaryl;  heterocyclyl;  C₃₋₇cycloalkyl-C₁₋₆alkyl;  aryl-C₁₋₆alkyl;  heteroaryl-C₁₋₆alkyl; or  heterocyclyl-C₁₋₆alkyl; or R⁴ and R⁵ together with the atom to which they are attached may form a C₃₋₆ carbocyclic ring that is optionally substituted with hydroxy; or R⁴ and R⁵ together with the atom to which they are attached may form a C₄₋₆ heterocyclic ring containing one or two heteroatoms each independently selected from O, N and S; or R³, R⁴ and R⁵ together with the atom to which they are attached may form a six-membered heteroaryl containing one or two nitrogen atoms, and which is optionally substituted with halo, amino or C₁₋₆alkyl; and R⁶, R⁷ and R⁸ each independently is: hydrogen C₁₋₆alkyl; C₁₋₆alkyloxy; halo; C₁₋₆haloalkyl; or cyano.
 2. The compound of claim 1, wherein R¹ is 1H-pyrazol-1-yl substituted once with C₁₋₆alkyl or halo-C₁₋₆alkyl.
 3. The compound of claim 1, wherein R² is phenyl substituted at the 4-position with methyl or halo and optionally substituted at the 2- and 6-positions with halo.
 4. The compound of claim 1, wherein R² is 4-methyl-phenyl, 2-fluoro-4-methyl-phenyl, 2-chloro-4-fluoro-phenyl, 4-chloro-2-fluoro-phenyl, 2,4-dichloro-phenyl, 2,4-difluoro-phenyl, or 2-chloro-4-methyl-phenyl.
 5. The compound of claim 1, wherein R² is pyridin-2-yl substituted with methyl or halo at the 5-position and optionally substituted with halo at the 3-position.
 6. The compound of claim 1, wherein R² is 5-methyl-pyridin-2-yl, 5-chloro-pyridin-2-yl, 5-fluoro-pyridin-2-yl, 5-methyl-3-fluoro-pyridin-2-yl, 5-methyl-3-chloro-pyridin-2-yl, 3,5-difluoro-pyridin-2-yl or 3,5-dichloro-ppyridin-2-yl.
 7. The compound of claim 1, wherein R⁶, R⁷ and R⁸ are hydrogen.
 8. The compound of claim 1, wherein R³ is hydrogen.
 9. The compound of claim 1, wherein R⁴ is hydrogen.
 10. The compound of claim 1, wherein R⁴ is methyl.
 11. The compound of claim 1, wherein R⁴ and R⁵ together with the atom to which they are attached form a C₃₋₆ carbocyclic ring that is optionally substituted with hydroxy.
 12. The compound of claim 1, wherein R⁵ is: C₁₋₆alkyl; C₁₋₆alkyloxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; C₁₋₆alkylsulfanyl-C₁₋₆alkyl; C₁₋₆alkylsulfonyl-C₁₋₆alkyl; amino-C₁₋₆alkyl; N—C₁₋₆alkyl-amino-C₁₋₆alkyl; N,N-di-C₁₋₆alkyl-amino-C₁₋₆alkyl; C₃₋₇cycloalkyl; optionally substituted phenyl; heteroaryl, or heterocyclyl-C₁₋₆alkyl.
 13. The compound of claim 1, wherein R⁵ is: C₁₋₆alkyloxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkyl; heteroaryl, or heterocyclyl-C₁₋₆alkyl.
 14. The compound of claim 1, wherein R⁵ is: is hydroxymethyl, methoxymethyl, pyrazin-2-yl, 5-methyl-pyrazin-2-yl, 6-methyl-pyridazin-3-yl, or 1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl.
 15. The compound of claim 1, wherein said compound is of formula IIa or IIb:

or a pharmaceutically acceptable salt thereof, wherein: X is C or N; R¹¹ and R¹² each independently is: hydrogen; C₁₋₆alkyl; C₁₋₆alkyloxy; halo; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; hetero-C₁₋₆alkyl; C₁₋₆alkylsulfonyl; or cyano; and R¹ and R⁵ are as recited in claim
 1. 16. The compound of claim 1, wherein said compound is of formula III:

or a pharmaceutically acceptable salt thereof, wherein: X is C or N; R¹¹ and R¹² each independently is: hydrogen; C₁₋₆alkyl; C₁₋₆alkyloxy; halo; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; hetero-C₁₋₆alkyl; C₁₋₆alkylsulfonyl; or cyano; and R¹ and R⁵ are as recited in claim
 1. 17. A pharmaceutical composition comprising: (a) a pharmaceutically acceptable carrier; and (b) a compound of claim
 1. 